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Soderling, Scott Haydn

Positions:

Associate Professor in Cell Biology

Cell Biology
School of Medicine

Associate Professor of Neurobiology

Neurobiology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

Ph.D. — University of Washington

Postdoctoral Fellow, Hhmi

Oregon Health and Science University

News:

Grants:

Molecular, Synaptic, and Circuit Basis for Schizophrenia-related Phenotypes

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 10, 2014
End Date
January 31, 2019

Unveiling Brain Circuits of Abnormal Social Behavior

Administered By
Cell Biology
AwardedBy
Brain and Behavior Research Foundation
Role
Principal Investigator
Start Date
January 15, 2017
End Date
January 14, 2019

Analysis of Arp2/3 activity as a major driver of dendritic spinogenesis

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2018

Fragile X Phenotypes Modulated by Altered Signaling to the Synaptic Cytoskeleton

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 15, 2014
End Date
January 31, 2018

Quantitative Analysis of the Postsynaptic Inhibitory Complex In Vivo

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2015
End Date
July 31, 2017

Basic predoctoral training in neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 1992
End Date
June 30, 2017

Synaptic plasticity

Administered By
Neurobiology
AwardedBy
Max Planck Institute
Role
Co Investigator
Start Date
November 01, 2013
End Date
December 31, 2016

Training in Fundamental &Translational Neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 2005
End Date
February 29, 2016

Fragile X Phenotypes Modulated by Altered Signaling to the Synaptic Cytoskeleton

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2007
End Date
February 14, 2014

Agilent Direct Drive 9.4T MRS/MRI Console

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
May 15, 2012
End Date
November 14, 2013

The effects of Nlrp12 and IL-1b in inflammatory disorders

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2010
End Date
February 29, 2012

Mapping the Architecture of Cancer Signaling Pathways

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2009
End Date
January 31, 2012
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Publications:

Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders?

Actin polymerization governs activity-dependent modulation of excitatory synapses, including their morphology and functionality. It is clear from human genetics that neuropsychiatric and neurodevelopmental disturbances are multigenetic in nature, highlighting the need to better understand the critical neural pathways associated with these disorders and how they are altered by genetic risk alleles. One such signaling pathway that is heavily implicated by candidate genes for psychiatric and neurodevelopmental disorders are regulators of signaling to the actin cytoskeleton, suggesting that its disruption and the ensuring abnormalities of spine structures and postsynaptic complexes is a commonly affected pathway in brain disorders. This review will discuss recent experimental findings that strongly support genetic evidence linking the synaptic cytoskeleton to mental disorders, such as schizophrenia and autism spectrum disorders.

Authors
Yan, Z; Kim, E; Datta, D; Lewis, DA; Soderling, SH
MLA Citation
Yan, Z, Kim, E, Datta, D, Lewis, DA, and Soderling, SH. "Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders?." November 2016.
PMID
27911743
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
36
Issue
45
Publish Date
2016
Start Page
11411
End Page
11417
DOI
10.1523/jneurosci.2360-16.2016

Identification of an elaborate complex mediating postsynaptic inhibition.

Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remain poorly understood. We used an in vivo chemico-genetic proximity-labeling approach to discover inhibitory postsynaptic proteins. Quantitative mass spectrometry not only recapitulated known inhibitory postsynaptic proteins but also revealed a large network of new proteins, many of which are either implicated in neurodevelopmental disorders or are of unknown function. Clustered regularly interspaced short palindromic repeats (CRISPR) depletion of one of these previously uncharacterized proteins, InSyn1, led to decreased postsynaptic inhibitory sites, reduced the frequency of miniature inhibitory currents, and increased excitability in the hippocampus. Our findings uncover a rich and functionally diverse assemblage of previously unknown proteins that regulate postsynaptic inhibition and might contribute to developmental brain disorders.

Authors
Uezu, A; Kanak, DJ; Bradshaw, TWA; Soderblom, EJ; Catavero, CM; Burette, AC; Weinberg, RJ; Soderling, SH
MLA Citation
Uezu, A, Kanak, DJ, Bradshaw, TWA, Soderblom, EJ, Catavero, CM, Burette, AC, Weinberg, RJ, and Soderling, SH. "Identification of an elaborate complex mediating postsynaptic inhibition." Science (New York, N.Y.) 353.6304 (September 2016): 1123-1129.
PMID
27609886
Source
epmc
Published In
Science
Volume
353
Issue
6304
Publish Date
2016
Start Page
1123
End Page
1129
DOI
10.1126/science.aag0821

The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing.

Dendritic filopodia are actin-rich structures that are thought to contribute to early spine synapse formation; however, the actin regulatory proteins important for early synaptogenesis are poorly defined. Using organotypic hippocampal slice cultures and primary neuron hippocampal cultures from Arp2/3 conditional knock-out mice, we analyze the roles of the Arp2/3 complex, an actin regulator that creates branched actin networks, and demonstrate it is essential for distinct stages of both structural and functional maturation of excitatory spine synapses. Our data show that initially the Arp2/3 complex inhibits the formation of dendritic filopodia but that later during development, the Arp2/3 complex drives the morphological maturation from filopodia to typical spine morphology. Furthermore, we demonstrate that although the Arp2/3 complex is not required for key spine maturation steps, such as presynaptic contact and recruitment of MAGUK (membrane-associated guanylate kinase) scaffolding proteins or NMDA receptors, it is necessary for the recruitment of AMPA receptors. This latter process, also known as synapse unsilencing, is a final and essential step in the neurodevelopment of excitatory postsynaptic synaptogenesis, setting the stage for neuronal interconnectivity. These findings provide the first evidence that the Arp2/3 complex is directly involved in functional maturation of dendritic spines during the developmental period of spinogenesis.Excitatory spine synapse formation (spinogenesis) is a poorly understood yet pivotal period of neurodevelopment that occurs within 2-3 weeks after birth. Neurodevelopmental disorders such as intellectual disability and autism are characterized by abnormal spine structure, which may arise from abnormal excitatory synaptogenesis. The initial stage of spinogenesis is thought to begin with the emergence of actin-rich dendritic filopodia that initiate contact with presynaptic axonal boutons. However, it remains enigmatic how actin cytoskeletal regulation directs dendritic filopodial emergence or their subsequent maturation into dendritic spines during development and on into adulthood. In this study, we provide the first evidence that the Arp2/3 complex, a key actin nucleator, is involved in distinct stages of spine formation and is required for synapse unsilencing.

Authors
Spence, EF; Kanak, DJ; Carlson, BR; Soderling, SH
MLA Citation
Spence, EF, Kanak, DJ, Carlson, BR, and Soderling, SH. "The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing." The Journal of neuroscience : the official journal of the Society for Neuroscience 36.37 (September 2016): 9696-9709.
PMID
27629719
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
36
Issue
37
Publish Date
2016
Start Page
9696
End Page
9709
DOI
10.1523/jneurosci.0876-16.2016

A GABAergic nigrotectal pathway for coordination of drinking behavior.

The contribution of basal ganglia outputs to consummatory behavior remains poorly understood. We recorded from the substantia nigra pars reticulata (SNR), the major basal ganglia output nucleus, during self-initiated drinking in mice. The firing rates of many lateral SNR neurons were time-locked to individual licks. These neurons send GABAergic projections to the deep layers of the orofacial region of the lateral tectum (superior colliculus, SC). Many tectal neurons were also time-locked to licking, but their activity was usually in antiphase with that of SNR neurons, suggesting inhibitory nigrotectal projections. We used optogenetics to selectively activate the GABAergic nigrotectal afferents in the deep layers of the SC. Photo-stimulation of the nigrotectal projections transiently inhibited the activity of the lick-related tectal neurons, disrupted their licking-related oscillatory pattern and suppressed self-initiated drinking. These results demonstrate that GABAergic nigrotectal projections have a crucial role in coordinating drinking behavior.

Authors
Rossi, MA; Li, HE; Lu, D; Kim, IH; Bartholomew, RA; Gaidis, E; Barter, JW; Kim, N; Cai, MT; Soderling, SH; Yin, HH
MLA Citation
Rossi, MA, Li, HE, Lu, D, Kim, IH, Bartholomew, RA, Gaidis, E, Barter, JW, Kim, N, Cai, MT, Soderling, SH, and Yin, HH. "A GABAergic nigrotectal pathway for coordination of drinking behavior." Nature neuroscience 19.5 (May 2016): 742-748.
PMID
27043290
Source
epmc
Published In
Nature Neuroscience
Volume
19
Issue
5
Publish Date
2016
Start Page
742
End Page
748
DOI
10.1038/nn.4285

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

Authors
Singh, SK; Stogsdill, JA; Pulimood, NS; Dingsdale, H; Kim, YH; Pilaz, L-J; Kim, IH; Manhaes, AC; Rodrigues, WS; Pamukcu, A; Enustun, E; Ertuz, Z; Scheiffele, P; Soderling, SH; Silver, DL; Ji, R-R; Medina, AE; Eroglu, C
MLA Citation
Singh, SK, Stogsdill, JA, Pulimood, NS, Dingsdale, H, Kim, YH, Pilaz, L-J, Kim, IH, Manhaes, AC, Rodrigues, WS, Pamukcu, A, Enustun, E, Ertuz, Z, Scheiffele, P, Soderling, SH, Silver, DL, Ji, R-R, Medina, AE, and Eroglu, C. "Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin." Cell 164.1-2 (January 2016): 183-196.
PMID
26771491
Source
epmc
Published In
Cell
Volume
164
Issue
1-2
Publish Date
2016
Start Page
183
End Page
196
DOI
10.1016/j.cell.2015.11.034

Actin out: Regulation of the synaptic cytoskeleton

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serveas aplatform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease.

Authors
Spence, EF; Soderling, SH
MLA Citation
Spence, EF, and Soderling, SH. "Actin out: Regulation of the synaptic cytoskeleton." Journal of Biological Chemistry 290.48 (November 27, 2015): 28613-28622. (Review)
Source
scopus
Published In
The Journal of biological chemistry
Volume
290
Issue
48
Publish Date
2015
Start Page
28613
End Page
28622
DOI
10.1074/jbcR115.655118

Actin Out: Regulation of the Synaptic Cytoskeleton.

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease.

Authors
Spence, EF; Soderling, SH
MLA Citation
Spence, EF, and Soderling, SH. "Actin Out: Regulation of the Synaptic Cytoskeleton." The Journal of biological chemistry 290.48 (November 2015): 28613-28622. (Review)
PMID
26453304
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
48
Publish Date
2015
Start Page
28613
End Page
28622
DOI
10.1074/jbc.r115.655118

CNS myelin wrapping is driven by actin disassembly.

Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes requires dynamic actin filament assembly by the Arp2/3 complex. Unexpectedly, subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins and rapid disassembly of the oligodendrocyte actin cytoskeleton and does not require Arp2/3. Inducing loss of actin filaments drives oligodendrocyte membrane spreading and myelin wrapping in vivo, and the actin disassembly factor gelsolin is required for normal wrapping. We show that myelin basic protein, a protein essential for CNS myelin wrapping whose role has been unclear, is required for actin disassembly, and its loss phenocopies loss of actin disassembly proteins. Together, these findings provide insight into the molecular mechanism of myelin wrapping and identify it as an actin-independent form of mammalian cell motility.

Authors
Zuchero, JB; Fu, M-M; Sloan, SA; Ibrahim, A; Olson, A; Zaremba, A; Dugas, JC; Wienbar, S; Caprariello, AV; Kantor, C; Leonoudakis, D; Lariosa-Willingham, K; Kronenberg, G; Gertz, K; Soderling, SH; Miller, RH; Barres, BA
MLA Citation
Zuchero, JB, Fu, M-M, Sloan, SA, Ibrahim, A, Olson, A, Zaremba, A, Dugas, JC, Wienbar, S, Caprariello, AV, Kantor, C, Leonoudakis, D, Lariosa-Willingham, K, Kronenberg, G, Gertz, K, Soderling, SH, Miller, RH, and Barres, BA. "CNS myelin wrapping is driven by actin disassembly." Developmental cell 34.2 (July 9, 2015): 152-167.
PMID
26166300
Source
epmc
Published In
Developmental Cell
Volume
34
Issue
2
Publish Date
2015
Start Page
152
End Page
167
DOI
10.1016/j.devcel.2015.06.011

Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.

Psychiatric and neurodevelopmental disorders may arise from anomalies in long-range neuronal connectivity downstream of pathologies in dendritic spines. However, the mechanisms that may link spine pathology to circuit abnormalities relevant to atypical behavior remain unknown. Using a mouse model to conditionally disrupt a critical regulator of the dendritic spine cytoskeleton, the actin-related protein 2/3 complex (Arp2/3), we report here a molecular mechanism that unexpectedly reveals the inter-relationship of progressive spine pruning, elevated frontal cortical excitation of pyramidal neurons and striatal hyperdopaminergia in a cortical-to-midbrain circuit abnormality. The main symptomatic manifestations of this circuit abnormality are psychomotor agitation and stereotypical behaviors, which are relieved by antipsychotics. Moreover, this antipsychotic-responsive locomotion can be mimicked in wild-type mice by optogenetic activation of this circuit. Collectively these results reveal molecular and neural-circuit mechanisms, illustrating how diverse pathologies may converge to drive behaviors relevant to psychiatric disorders.

Authors
Kim, IH; Rossi, MA; Aryal, DK; Racz, B; Kim, N; Uezu, A; Wang, F; Wetsel, WC; Weinberg, RJ; Yin, H; Soderling, SH
MLA Citation
Kim, IH, Rossi, MA, Aryal, DK, Racz, B, Kim, N, Uezu, A, Wang, F, Wetsel, WC, Weinberg, RJ, Yin, H, and Soderling, SH. "Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine." Nature neuroscience 18.6 (June 2015): 883-891.
PMID
25938885
Source
epmc
Published In
Nature Neuroscience
Volume
18
Issue
6
Publish Date
2015
Start Page
883
End Page
891
DOI
10.1038/nn.4015

Restored WAVE1 Levels in a Model of NMDA Receptor Hypofunction Attenuates Working Memory Deficits

Authors
Chen, Y; Milenkovic, M; Soderling, SH; Ramsey, AJ
MLA Citation
Chen, Y, Milenkovic, M, Soderling, SH, and Ramsey, AJ. "Restored WAVE1 Levels in a Model of NMDA Receptor Hypofunction Attenuates Working Memory Deficits." May 1, 2015.
Source
wos-lite
Published In
Biological Psychiatry
Volume
77
Issue
9
Publish Date
2015

CNS Myelin Wrapping Is Driven by Actin Disassembly [Developmental Cell 34, 152-167; 27 July 2015]

Authors
Zuchero, JB; Fu, MM; Sloan, SA; Ibrahim, A; Olson, A; Zaremba, A; Dugas, JC; Wienbar, S; Caprariello, AV; Kantor, C; Leonoudakis, D; Lariosa-Willingham, K; Kronenberg, G; Gertz, K; Soderling, SH; Miller, RH; Barres, BA
MLA Citation
Zuchero, JB, Fu, MM, Sloan, SA, Ibrahim, A, Olson, A, Zaremba, A, Dugas, JC, Wienbar, S, Caprariello, AV, Kantor, C, Leonoudakis, D, Lariosa-Willingham, K, Kronenberg, G, Gertz, K, Soderling, SH, Miller, RH, and Barres, BA. "CNS Myelin Wrapping Is Driven by Actin Disassembly [Developmental Cell 34, 152-167; 27 July 2015]." Developmental Cell 34.5 (January 1, 2015): 608-.
Source
scopus
Published In
Developmental Cell
Volume
34
Issue
5
Publish Date
2015
Start Page
608
DOI
10.1016/j.devcel.2015.08.013

Astrocytes refine cortical connectivity at dendritic spines.

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.

Authors
Risher, WC; Patel, S; Kim, IH; Uezu, A; Bhagat, S; Wilton, DK; Pilaz, L-J; Singh Alvarado, J; Calhan, OY; Silver, DL; Stevens, B; Calakos, N; Soderling, SH; Eroglu, C
MLA Citation
Risher, WC, Patel, S, Kim, IH, Uezu, A, Bhagat, S, Wilton, DK, Pilaz, L-J, Singh Alvarado, J, Calhan, OY, Silver, DL, Stevens, B, Calakos, N, Soderling, SH, and Eroglu, C. "Astrocytes refine cortical connectivity at dendritic spines." eLife 3 (December 17, 2014).
Website
http://hdl.handle.net/10161/9362
PMID
25517933
Source
epmc
Published In
eLife
Volume
3
Publish Date
2014
DOI
10.7554/elife.04047

Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall

Authors
Kim, IH; Wang, H; Soderling, SH; Yasuda, R
MLA Citation
Kim, IH, Wang, H, Soderling, SH, and Yasuda, R. "Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall." ELIFE 3 (August 1, 2014).
Source
wos-lite
Published In
eLife
Volume
3
Publish Date
2014
DOI
10.7554/eLife.02839

Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.

Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report that postnatal forebrain deletion of Cdc42 leads to deficits in synaptic plasticity and in remote memory recall using conditional knockout of Cdc42. We found that deletion of Cdc42 impaired LTP in the Schaffer collateral synapses and postsynaptic structural plasticity of dendritic spines in CA1 pyramidal neurons in the hippocampus. Additionally, loss of Cdc42 did not affect memory acquisition, but instead significantly impaired remote memory recall. Together these results indicate that the postnatal functions of Cdc42 may be crucial for the synaptic plasticity in hippocampal neurons, which contribute to the capacity for remote memory recall.

Authors
Kim, IH; Wang, H; Soderling, SH; Yasuda, R
MLA Citation
Kim, IH, Wang, H, Soderling, SH, and Yasuda, R. "Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall." eLife 3 (July 8, 2014).
PMID
25006034
Source
epmc
Published In
eLife
Volume
3
Publish Date
2014
DOI
10.7554/elife.02839

Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall

Authors
Kim, IH; Wang, H; Soderling, SH; Yasuda, R
MLA Citation
Kim, IH, Wang, H, Soderling, SH, and Yasuda, R. "Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall." ELIFE 3 (July 8, 2014).
Source
wos-lite
Published In
eLife
Volume
3
Publish Date
2014
DOI
10.7554/eLife.02839

Principles driving the spatial organization of Rho GTPase signaling at synapses

© 2014 Springer-Verlag Wien. All rights reserved.The Rho proteins play critical roles in numerous aspects of neuronal development, and mutations in their regulators (GEFs and GAPs) and effectors underlie multiple neurodevelopmental and neurological disorders. How Rho GTPase-mediated signaling can have a hand in regulating so many different neurobiological processes remains a challenging question. An emerging theme is that GAPs and GEFs, through their spatial/temporal regulation and/or through additional protein-protein interactions, cooperate in making connections between upstream signals and the downstream signaling output, engaging distinct effector proteins. This chapter focuses on recent evidence illustrating distinct modes of regulation and specialized roles of Rho regulators particularly in the context of synaptic structure, function, and plasticity, and how their dysregulation affects behavioral processes and contributes to disease.

Authors
Soderling, SH; Van Aelst, L
MLA Citation
Soderling, SH, and Van Aelst, L. "Principles driving the spatial organization of Rho GTPase signaling at synapses." Ras Superfamily Small G Proteins: Biology and Mechanisms 1: General Features, Signaling. May 1, 2014. 395-419.
Source
scopus
Publish Date
2014
Start Page
395
End Page
419
DOI
10.1007/978-3-7091-1806-1_17

Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation.

The epidermis provides an essential seal from the external environment and retains fluids within the body. To form an effective barrier, cells in the epidermis must form tight junctions and terminally differentiate into cornified envelopes. Here, we demonstrate that the branched actin nucleator, the actin-related protein (Arp)2/3 complex, is unexpectedly required for both these activities. Loss of the ArpC3 subunit of the Arp2/3 complex resulted in minimal changes in the morphogenesis and architecture of this stratified squamous epithelium, but resulted in profound defects in its physiology. Mutant embryos did not develop an effective barrier to the external environment and died within hours of birth. We discovered two underlying causes for these effects. First, ArpC3 was essential for robust assembly and function of tight junctions, specialized cell-cell adhesions that restrict water loss in the epidermis. Second, there were defects in differentiation of the epidermis and the production of cornified envelopes, structures essential for barrier activity. Underlying this defect, we found that YAP was inappropriately active not only in the ArpC3 mutant tissue, but also in cultured cells. Inhibition of YAP activity rescued the differentiation and barrier defects caused by loss of ArpC3. These results demonstrate previously unappreciated roles for the Arp2/3 complex and highlight the functions of branched actin networks in a complex tissue.

Authors
Zhou, K; Muroyama, A; Underwood, J; Leylek, R; Ray, S; Soderling, SH; Lechler, T
MLA Citation
Zhou, K, Muroyama, A, Underwood, J, Leylek, R, Ray, S, Soderling, SH, and Lechler, T. "Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation." Proc Natl Acad Sci U S A 110.40 (October 1, 2013): E3820-E3829.
PMID
24043783
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
40
Publish Date
2013
Start Page
E3820
End Page
E3829
DOI
10.1073/pnas.1308419110

Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities.

Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known genetic risk factors for psychiatric disease are related to the regulation of actin polymerization, which plays a key role in synaptic plasticity. To gain insight into and test the possible pathogenetic role of this pathway, we designed a conditional knock-out of the Arp2/3 complex, a conserved final output for actin signaling pathways that orchestrates de novo actin polymerization. Here we report that postnatal loss of the Arp2/3 subunit ArpC3 in forebrain excitatory neurons leads to an asymmetric structural plasticity of dendritic spines, followed by a progressive loss of spine synapses. This progression of synaptic deficits corresponds with an evolution of distinct cognitive, psychomotor, and social disturbances as the mice age. Together, these results point to the dysfunction of actin signaling, specifically that which converges to regulate Arp2/3, as an important cellular pathway that may contribute to the etiology of complex psychiatric disorders.

Authors
Kim, IH; Racz, B; Wang, H; Burianek, L; Weinberg, R; Yasuda, R; Wetsel, WC; Soderling, SH
MLA Citation
Kim, IH, Racz, B, Wang, H, Burianek, L, Weinberg, R, Yasuda, R, Wetsel, WC, and Soderling, SH. "Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities." J Neurosci 33.14 (April 3, 2013): 6081-6092.
PMID
23554489
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
33
Issue
14
Publish Date
2013
Start Page
6081
End Page
6092
DOI
10.1523/JNEUROSCI.0035-13.2013

Under lock and key: spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes.

WASP family proteins are nucleation promoting factors that bind to and activate the Arp2/3 complex in order to stimulate nucleation of branched actin filaments. The WASP family consists of WASP, N-WASP, WAVE1-3, WASH, and the novel family members WHAMM and JMY. Each of the family members contains a C-terminus responsible for their nucleation promoting activity and unique N-termini that allow for them to be regulated in a spatiotemporal manner. Upon activation they reorganize the cytoskeleton for different cellular functions depending on their subcellular localization and regulatory protein interactions. Emerging evidence indicates that WASH, WHAMM, and JMY have functions that require the coordination of both actin polymerization and microtubule dynamics. Here, we review the mechanisms of regulation for each family member and their associated in vivo functions including cell migration, vesicle trafficking, and neuronal development.

Authors
Burianek, LE; Soderling, SH
MLA Citation
Burianek, LE, and Soderling, SH. "Under lock and key: spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes." Semin Cell Dev Biol 24.4 (April 2013): 258-266. (Review)
PMID
23291261
Source
pubmed
Published In
Seminars in Cell and Developmental Biology
Volume
24
Issue
4
Publish Date
2013
Start Page
258
End Page
266
DOI
10.1016/j.semcdb.2012.12.005

Under lock and key: Spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes

WASP family proteins are nucleation promoting factors that bind to and activate the Arp2/3 complex in order to stimulate nucleation of branched actin filaments. The WASP family consists of WASP, N-WASP, WAVE1-3, WASH, and the novel family members WHAMM and JMY. Each of the family members contains a C-terminus responsible for their nucleation promoting activity and unique N-termini that allow for them to be regulated in a spatiotemporal manner. Upon activation they reorganize the cytoskeleton for different cellular functions depending on their subcellular localization and regulatory protein interactions. Emerging evidence indicates that WASH, WHAMM, and JMY have functions that require the coordination of both actin polymerization and microtubule dynamics. Here, we review the mechanisms of regulation for each family member and their associated in vivo functions including cell migration, vesicle trafficking, and neuronal development. © 2013 Elsevier Ltd.

Authors
Burianek, LE; Soderling, SH
MLA Citation
Burianek, LE, and Soderling, SH. "Under lock and key: Spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes." Seminars in Cell and Developmental Biology 24.4 (2013): 258-266.
Source
scival
Published In
Seminars in Cell and Developmental Biology
Volume
24
Issue
4
Publish Date
2013
Start Page
258
End Page
266
DOI
10.1016/j.semcdb.2012.12.005

Ultrastructural abnormalities in CA1 hippocampus caused by deletion of the actin regulator WAVE-1.

By conveying signals from the small GTPase family of proteins to the Arp2/3 complex, proteins of the WAVE family facilitate actin remodeling. The WAVE-1 isoform is expressed at high levels in brain, where it plays a role in normal synaptic processing, and is implicated in hippocampus-dependent memory retention. We used electron microscopy to determine whether synaptic structure is modified in the hippocampus of WAVE-1 knockout mice, focusing on the neuropil of CA1 stratum radiatum. Mice lacking WAVE-1 exhibited alterations in the morphology of both axon terminals and dendritic spines; the relationship between the synaptic partners was also modified. The abnormal synaptic morphology we observed suggests that signaling through WAVE-1 plays a critical role in establishing normal synaptic architecture in the rodent hippocampus.

Authors
Hazai, D; Szudoczki, R; Ding, J; Soderling, SH; Weinberg, RJ; Sótonyi, P; Rácz, B
MLA Citation
Hazai, D, Szudoczki, R, Ding, J, Soderling, SH, Weinberg, RJ, Sótonyi, P, and Rácz, B. "Ultrastructural abnormalities in CA1 hippocampus caused by deletion of the actin regulator WAVE-1. (Published online)" PLoS One 8.9 (2013): e75248-.
PMID
24086480
Source
pubmed
Published In
PloS one
Volume
8
Issue
9
Publish Date
2013
Start Page
e75248
DOI
10.1371/journal.pone.0075248

Disruption of wave-associated Rac GTPase-activating protein (Wrp) leads to abnormal adult neural progenitor migration associated with hydrocephalus.

Hydrocephalus is the most common developmental disability and leading cause of brain surgery for children. Current treatments are limited to surgical intervention, as the factors that contribute to the initiation of hydrocephalus are poorly understood. Here, we describe the development of obstructive hydrocephalus in mice that are null for Wrp (Srgap3). Wrp is highly expressed in the ventricular stem cell niche, and it is a gene required for cytoskeletal organization and is associated with syndromic and psychiatric disorders in humans. During the postnatal period of progenitor cell expansion and ventricular wall remodeling, loss of Wrp results in the abnormal migration of lineage-tagged cells from the ventricular region into the corpus callosum. Within this region, mutant progenitors appear to give rise to abnormal astroglial cells and induce periventricular lesions and hemorrhage that leads to cerebral aqueductal occlusion. These results indicate that periventricular abnormalities arising from abnormal migration from the ventricular niche can be an initiating cause of noncommunicating hydrocephalus.

Authors
Kim, IH; Carlson, BR; Heindel, CC; Kim, H; Soderling, SH
MLA Citation
Kim, IH, Carlson, BR, Heindel, CC, Kim, H, and Soderling, SH. "Disruption of wave-associated Rac GTPase-activating protein (Wrp) leads to abnormal adult neural progenitor migration associated with hydrocephalus." J Biol Chem 287.46 (November 9, 2012): 39263-39274.
PMID
23007397
Source
pubmed
Published In
The Journal of biological chemistry
Volume
287
Issue
46
Publish Date
2012
Start Page
39263
End Page
39274
DOI
10.1074/jbc.M112.398834

Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells.

Spatial regulation of tyrosine phosphorylation is important for many aspects of cell biology. However, phosphotyrosine accounts for less than 1% of all phosphorylated substrates, and it is typically a very transient event in vivo. These factors complicate the identification of key tyrosine kinase substrates, especially in the context of their extraordinary spatial organization. Here, we describe an approach to identify tyrosine kinase substrates based on their subcellular distribution from within cells. This method uses an unnatural amino acid-modified Src homology 2 (SH2) domain that is expressed within cells and can covalently trap phosphotyrosine proteins on exposure to light. This SH2 domain-based photoprobe was targeted to cellular structures, such as the actin cytoskeleton, mitochondria, and cellular membranes, to capture tyrosine kinase substrates unique to each cellular region. We demonstrate that RhoA, one of the proteins associated with actin, can be phosphorylated on two tyrosine residues within the switch regions, suggesting that phosphorylation of these residues might modulate RhoA signaling to the actin cytoskeleton. We conclude that expression of SH2 domains within cellular compartments that are capable of covalent phototrapping can reveal the spatial organization of tyrosine kinase substrates that are likely to be important for the regulation of subcellular structures.

Authors
Uezu, A; Okada, H; Murakoshi, H; del Vescovo, CD; Yasuda, R; Diviani, D; Soderling, SH
MLA Citation
Uezu, A, Okada, H, Murakoshi, H, del Vescovo, CD, Yasuda, R, Diviani, D, and Soderling, SH. "Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells." Proc Natl Acad Sci U S A 109.43 (October 23, 2012): E2929-E2938.
PMID
23027962
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
43
Publish Date
2012
Start Page
E2929
End Page
E2938
DOI
10.1073/pnas.1207358109

Peptide array X-linking (PAX): a new peptide-protein identification approach.

Many protein interaction domains bind short peptides based on canonical sequence consensus motifs. Here we report the development of a peptide array-based proteomics tool to identify proteins directly interacting with ligand peptides from cell lysates. Array-formatted bait peptides containing an amino acid-derived cross-linker are photo-induced to crosslink with interacting proteins from lysates of interest. Indirect associations are removed by high stringency washes under denaturing conditions. Covalently trapped proteins are subsequently identified by LC-MS/MS and screened by cluster analysis and domain scanning. We apply this methodology to peptides with different proline-containing consensus sequences and show successful identifications from brain lysates of known and novel proteins containing polyproline motif-binding domains such as EH, EVH1, SH3, WW domains. These results suggest the capacity of arrayed peptide ligands to capture and subsequently identify proteins by mass spectrometry is relatively broad and robust. Additionally, the approach is rapid and applicable to cell or tissue fractions from any source, making the approach a flexible tool for initial protein-protein interaction discovery.

Authors
Okada, H; Uezu, A; Soderblom, EJ; Moseley, MA; Gertler, FB; Soderling, SH
MLA Citation
Okada, H, Uezu, A, Soderblom, EJ, Moseley, MA, Gertler, FB, and Soderling, SH. "Peptide array X-linking (PAX): a new peptide-protein identification approach." PLoS One 7.5 (2012): e37035-.
PMID
22606326
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e37035
DOI
10.1371/journal.pone.0037035

SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes.

Rho family GAPs [guanosine triphosphatase (GTPase) activating proteins] negatively regulate Rho family GTPase activity and therefore modulate signaling events that control cytoskeletal dynamics. The spatial distribution of these GAPs and their specificity toward individual GTPases are controlled by their interactions with various proteins within signaling complexes. These interactions are likely mediated through the Src homology 3 (SH3) domain, which is abundant in the Rho family GAP proteome and exhibits a micromolar binding affinity, enabling the Rho family GAPs to participate in transient interactions with multiple binding partners. To capture these elusive GAP signaling complexes in situ, we developed a domain-based proteomics approach, starting with in vivo phototrapping of SH3 domain-binding proteins and the mass spectrometry identification of associated proteins for nine representative Rho family GAPs. After the selection of candidate binding proteins by cluster analysis, we performed peptide array-based high-throughput in vitro binding assays to confirm the direct interactions and map the SH3 domain-binding sequences. We thereby identified 54 SH3-mediated binding interactions (including 51 previously unidentified ones) for nine Rho family GAPs. We constructed Rho family GAP interactomes that provided insight into the functions of these GAPs. We further characterized one of the predicted functions for the Rac-specific GAP WRP and identified a role for WRP in mediating clustering of the postsynaptic scaffolding protein gephyrin and the GABA(A) (γ-aminobutyric acid type A) receptor at inhibitory synapses.

Authors
Okada, H; Uezu, A; Mason, FM; Soderblom, EJ; Moseley, MA; Soderling, SH
MLA Citation
Okada, H, Uezu, A, Mason, FM, Soderblom, EJ, Moseley, MA, and Soderling, SH. "SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes. (Published online)" Sci Signal 4.201 (November 29, 2011): rs13-.
PMID
22126966
Source
pubmed
Published In
Science Signaling
Volume
4
Issue
201
Publish Date
2011
Start Page
rs13
DOI
10.1126/scisignal.2002189

Bi-modal regulation of a formin by srGAP2.

The maintenance of rapid and efficient actin dynamics in vivo requires coordination of filament assembly and disassembly. This regulation requires temporal and spatial integration of signaling pathways by protein complexes. However, it remains unclear how these complexes form and then regulate the actin cytoskeleton. Here, we identify a srGAP2 and formin-like 1 (FMNL1, also known as FRL1 or FRLα) complex whose assembly is regulated by Rac signaling. Our data suggest srGAP2 regulates FMNL1 in two ways; 1) Rac-mediated activation of FMNL1 leads to the recruitment of srGAP2, which contains a Rac-specific GAP domain; 2) the SH3 domain of srGAP2 binds the formin homology 1 domain of FMNL1 to inhibit FMNL1-mediated actin severing. Thus, srGAP2 can efficiently terminate the upstream activating Rac signal while also opposing an important functional output of FMNL1, namely actin severing. We also show that FMNL1 and srGAP2 localize to the actin-rich phagocytic cup of macrophage-derived cells, suggesting the complex may regulate this Rac- and actin-driven process in vivo. We propose that after Rac-dependent activation of FMNL1, srGAP2 mediates a potent mechanism to limit the duration of Rac action and inhibit formin activity during rapid actin dynamics.

Authors
Mason, FM; Heimsath, EG; Higgs, HN; Soderling, SH
MLA Citation
Mason, FM, Heimsath, EG, Higgs, HN, and Soderling, SH. "Bi-modal regulation of a formin by srGAP2." J Biol Chem 286.8 (February 25, 2011): 6577-6586.
PMID
21148482
Source
pubmed
Published In
The Journal of biological chemistry
Volume
286
Issue
8
Publish Date
2011
Start Page
6577
End Page
6586
DOI
10.1074/jbc.M110.190397

WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory.

The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory.

Authors
Carlson, BR; Lloyd, KE; Kruszewski, A; Kim, I-H; Rodriguiz, RM; Heindel, C; Faytell, M; Dudek, SM; Wetsel, WC; Soderling, SH
MLA Citation
Carlson, BR, Lloyd, KE, Kruszewski, A, Kim, I-H, Rodriguiz, RM, Heindel, C, Faytell, M, Dudek, SM, Wetsel, WC, and Soderling, SH. "WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory." J Neurosci 31.7 (February 16, 2011): 2447-2460.
PMID
21325512
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
31
Issue
7
Publish Date
2011
Start Page
2447
End Page
2460
DOI
10.1523/JNEUROSCI.4433-10.2011

SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes.

Rho family GAPs [guanosine triphosphatase (GTPase) activating proteins] negatively regulate Rho family GTPase activity and therefore modulate signaling events that control cytoskeletal dynamics. The spatial distribution of these GAPs and their specificity toward individual GTPases are controlled by their interactions with various proteins within signaling complexes. These interactions are likely mediated through the Src homology 3 (SH3) domain, which is abundant in the Rho family GAP proteome and exhibits a micromolar binding affinity, enabling the Rho family GAPs to participate in transient interactions with multiple binding partners. To capture these elusive GAP signaling complexes in situ, we developed a domain-based proteomics approach, starting with in vivo phototrapping of SH3 domain-binding proteins and the mass spectrometry identification of associated proteins for nine representative Rho family GAPs. After the selection of candidate binding proteins by cluster analysis, we performed peptide array-based high-throughput in vitro binding assays to confirm the direct interactions and map the SH3 domain-binding sequences. We thereby identified 54 SH3-mediated binding interactions (including 51 previously unidentified ones) for nine Rho family GAPs. We constructed Rho family GAP interactomes that provided insight into the functions of these GAPs. We further characterized one of the predicted functions for the Rac-specific GAP WRP and identified a role for WRP in mediating clustering of the postsynaptic scaffolding protein gephyrin and the GABA(A) (γ-aminobutyric acid type A) receptor at inhibitory synapses.

Authors
Okada, H; Uezu, A; Mason, FM; Soderblom, EJ; 3rd, MAM; Soderling, SH
MLA Citation
Okada, H, Uezu, A, Mason, FM, Soderblom, EJ, 3rd, MAM, and Soderling, SH. "SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes." Science signaling 4.201 (2011): rs13-.
Source
scival
Published In
Science Signaling
Volume
4
Issue
201
Publish Date
2011
Start Page
rs13
DOI
10.1126/scisignal.2002189

Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders.

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during experience-dependent plasticity. This mini-symposium review will feature ongoing research into how spines are regulated by actin-signaling pathways during development and plasticity. It will also highlight evolving studies into how disruptions to these pathways might be functionally coupled to congenital disorders such as mental retardation.

Authors
Svitkina, T; Lin, W-H; Webb, DJ; Yasuda, R; Wayman, GA; Van Aelst, L; Soderling, SH
MLA Citation
Svitkina, T, Lin, W-H, Webb, DJ, Yasuda, R, Wayman, GA, Van Aelst, L, and Soderling, SH. "Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders." J Neurosci 30.45 (November 10, 2010): 14937-14942. (Review)
PMID
21068295
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
30
Issue
45
Publish Date
2010
Start Page
14937
End Page
14942
DOI
10.1523/JNEUROSCI.4276-10.2010

WASP and WAVE family protein complexes

Arp2/3 is inactive and is unable to trigger de novo actin polymerization. It must be activated by binding to members of the WASP/WAVE family of scaffold proteins to effectively stimulate actin polymerization. The WASP/WAVE family members (WASP, N-WASP, WAVE-1, WAVE-2, and WAVE-3) are activated by Cdc42 and Rac. Thus, a linear pathway (Cdc42/Rac→WASP/WAVE→Arp2/3) translates cellular cues into the assembly of actin filaments. Protein complexes organized by the WASP/WAVE proteins, however, modulate this basic pathway. This chapter summarizes how the WASP and WAVE family protein complexes are organized and are thought to function. WASP/N-WASP and WAVE proteins function as scaffolds to organize protein complexes that modulate dynamic actin turnover through Arp2/3. These protein complexes serve to optimize subcellular targeting of WASP/WAVE, and to act as positive and negative feedback information loops to regulate actin dynamics. Thus, these complexes are likely to serve as sophisticated non-linear signaling pathways that function between Rho-GTPases and Arp2/3. Components of the WASP and WAVE complexes may also function to tie actin regulation to other pathways by interacting with separate protein complexes. Finally, it is likely that new regulatory complexes await discovery. In this regard, WASH (Wiskott-Aldrich Syndrome Protein and SCAR Homolog) has recently been identified as a potential new member of the WASP/WAVE family of Arp2/3 activators. © 2010 Elsevier Inc. All rights reserved.

Authors
Mason, FM; Soderling, SH
MLA Citation
Mason, FM, and Soderling, SH. "WASP and WAVE family protein complexes." Handbook of Cell Signaling, 2/e 2 (2010): 1265-1270.
Source
scival
Published In
Handbook of Cell Signaling, 2/e
Volume
2
Publish Date
2010
Start Page
1265
End Page
1270
DOI
10.1016/B978-0-12-374145-5.00157-1

Inositol 1,4,5-trisphosphate 3-kinase a functions as a scaffold for synaptic Rac signaling.

Activity-dependent alterations of synaptic contacts are crucial for synaptic plasticity. The formation of new dendritic spines and synapses is known to require actin cytoskeletal reorganization specifically during neural activation phases. Yet the site-specific and time-dependent mechanisms modulating actin dynamics in mature neurons are not well understood. In this study, we show that actin dynamics in spines is regulated by a Rac anchoring and targeting function of inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A), independent of its kinase activity. On neural activation, IP(3)K-A bound directly to activated Rac1 and recruited it to the actin cytoskeleton in the postsynaptic area. This focal targeting of activated Rac1 induced spine formation through actin dynamics downstream of Rac signaling. Consistent with the scaffolding role of IP(3)K-A, IP(3)K-A knock-out mice exhibited defects in accumulation of PAK1 by long-term potentiation-inducing stimulation. This deficiency resulted in a reduction in the reorganization of actin cytoskeletal structures in the synaptic area of dentate gyrus. Moreover, IP(3)K-A knock-out mice showed deficits of synaptic plasticity in perforant path and in hippocampal-dependent memory performances. These data support a novel model in which IP(3)K-A is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism.

Authors
Kim, IH; Park, SK; Hong, ST; Jo, YS; Kim, EJ; Park, EH; Han, SB; Shin, H-S; Sun, W; Kim, HT; Soderling, SH; Kim, H
MLA Citation
Kim, IH, Park, SK, Hong, ST, Jo, YS, Kim, EJ, Park, EH, Han, SB, Shin, H-S, Sun, W, Kim, HT, Soderling, SH, and Kim, H. "Inositol 1,4,5-trisphosphate 3-kinase a functions as a scaffold for synaptic Rac signaling." J Neurosci 29.44 (November 4, 2009): 14039-14049.
PMID
19890013
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
29
Issue
44
Publish Date
2009
Start Page
14039
End Page
14049
DOI
10.1523/JNEUROSCI.2483-09.2009

Mechanisms of cellular protrusions branch out.

F-BAR domains bind curved membranes and induce membrane invagination. In a recent Cell paper, Guerrier et al. describe an "inverse" F-BAR family member that induces outward curvature and filopodia in migrating neurons. These findings suggest that F-BAR domains are functionally diverse and regulate different types of membrane morphology.

Authors
Carlson, B; Soderling, SH
MLA Citation
Carlson, B, and Soderling, SH. "Mechanisms of cellular protrusions branch out." Dev Cell 17.3 (September 2009): 307-309.
PMID
19758555
Source
pubmed
Published In
Developmental Cell
Volume
17
Issue
3
Publish Date
2009
Start Page
307
End Page
309
DOI
10.1016/j.devcel.2009.08.015

Grab your partner with both hands: cytoskeletal remodeling by Arp2/3 signaling.

The seemingly simple structure of the actin filament belies the elaborate signaling pathways that regulate its assembly and disassembly in eukaryotic cells. In retrospect, this signaling complexity should not be surprising. Actin regulates many dynamic cellular processes, including protein and organelle trafficking, establishment of cell polarity, directional migration, cellular traction, and the efficiency of endocytosis. Signaling events that coordinately control actin turnover during these processes must display a high degree of sophistication. Emerging data on an important regulator of actin dynamics, the actin-related protein 2 and 3 (Arp2/3) complex, suggest a model of how this may occur.

Authors
Soderling, SH
MLA Citation
Soderling, SH. "Grab your partner with both hands: cytoskeletal remodeling by Arp2/3 signaling. (Published online)" Sci Signal 2.55 (January 27, 2009): pe5-. (Review)
PMID
19176514
Source
pubmed
Published In
Science Signaling
Volume
2
Issue
55
Publish Date
2009
Start Page
pe5
DOI
10.1126/scisignal.255pe5

A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory.

The scaffolding protein WAVE-1 (Wiskott-Aldrich syndrome protein family member 1) directs signals from the GTPase Rac through the Arp2/3 complex to facilitate neuronal actin remodeling. The WAVE-associated GTPase activating protein called WRP is implicated in human mental retardation, and WAVE-1 knock-out mice have altered behavior. Neuronal time-lapse imaging, behavioral analyses, and electrophysiological recordings from genetically modified mice were used to show that WAVE-1 signaling complexes control aspects of neuronal morphogenesis and synaptic plasticity. Gene targeting experiments in mice demonstrate that WRP anchoring to WAVE-1 is a homeostatic mechanism that contributes to neuronal development and the fidelity of synaptic connectivity. This implies that signaling through WAVE-1 complexes is essential for neural plasticity and cognitive behavior.

Authors
Soderling, SH; Guire, ES; Kaech, S; White, J; Zhang, F; Schutz, K; Langeberg, LK; Banker, G; Raber, J; Scott, JD
MLA Citation
Soderling, SH, Guire, ES, Kaech, S, White, J, Zhang, F, Schutz, K, Langeberg, LK, Banker, G, Raber, J, and Scott, JD. "A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory." J Neurosci 27.2 (January 10, 2007): 355-365.
PMID
17215396
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
27
Issue
2
Publish Date
2007
Start Page
355
End Page
365
DOI
10.1523/JNEUROSCI.3209-06.2006

WAVE signalling: from biochemistry to biology.

The small GTPases Rho, Rac and Cdc42 (cell-division cycle 42) function as molecular switches to modulate the actin cytoskeleton. They achieve this by modulating the activity of downstream cellular targets. One group of Rho GTPase effectors, WAVE (Wiskott-Aldrich syndrome protein verprolin homologous)-1, WAVE-2 and WAVE-3, function as scaffolds for actin-based signalling complexes. The present review highlights current knowledge regarding the biochemistry of the WAVE signalling complexes and their biological significance.

Authors
Soderling, SH; Scott, JD
MLA Citation
Soderling, SH, and Scott, JD. "WAVE signalling: from biochemistry to biology." Biochem Soc Trans 34.Pt 1 (February 2006): 73-76. (Review)
PMID
16417486
Source
pubmed
Published In
Biochemical Society transactions
Volume
34
Issue
Pt 1
Publish Date
2006
Start Page
73
End Page
76
DOI
10.1042/BST0340073

Identification of a new variant of PDE1A calmodulin-stimulated cyclic nucleotide phosphodiesterase expressed in mouse sperm.

In mature sperm, cAMP plays an important role as a second messenger regulating functions that include capacitation, the acrosome reaction, motility, and, in some cases, chemosensing. We have cloned from mouse testis a novel calmodulin-stimulated cyclic nucleotide phosphodiesterase 1A isoform, Pde1a_v7 (mmPDE1A7), which arises from an alternative transcription start in the cyclic nucleotide phosphodiesterase 1A gene. The open reading frame is predicted to encode a polypeptide with a molecular mass of 52 kDa. Two further variants of this form, which contain two additional new exons, arise from alternative splicing. Analysis of testis cDNA by real-time polymerase chain reaction (PCR) indicates that the Pde1A_v7 transcript variant is the most abundant. The PDE1A_v7 protein uniquely lacks the first amino-terminal calmodulin-binding domain, but does possess an inhibitory domain and a second calmodulin-binding site shared with other variants. In vitro translation of the corresponding Pde1a_v7 cDNA produced a 52-kDa polypeptide having cyclic nucleotide hydrolytic activity, which was stimulated threefold by calcium-bound calmodulin. Immunoprecipitation of cyclic nucleotide phosphodiesterase 1 activity from detergent extracts of mouse sperm revealed a major protein of the size expected for PDE1A_v7, and the immunocytochemical staining for cyclic nucleotide phosphodiesterase 1A in mouse sperm showed intense immunoreactivity in the tail only. These observations, along with the PCR data, strongly suggest that this new variant PDE1A_v7 is the major form of cyclic nucleotide phosphodiesterase 1A expressed in mature sperm and is therefore likely to play an important role in cyclic nucleotide regulation of mature sperm function.

Authors
Vasta, V; Sonnenburg, WK; Yan, C; Soderling, SH; Shimizu-Albergine, M; Beavo, JA
MLA Citation
Vasta, V, Sonnenburg, WK, Yan, C, Soderling, SH, Shimizu-Albergine, M, and Beavo, JA. "Identification of a new variant of PDE1A calmodulin-stimulated cyclic nucleotide phosphodiesterase expressed in mouse sperm." Biol Reprod 73.4 (October 2005): 598-609.
PMID
15901640
Source
pubmed
Published In
Biology of Reproduction
Volume
73
Issue
4
Publish Date
2005
Start Page
598
End Page
609
DOI
10.1095/biolreprod.104.039180

Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring.

Compartmentalization of the cAMP-dependent protein kinase (PKA) is coordinated through association with A-kinase anchoring proteins (AKAPs). A defining characteristic of most AKAPs is a 14- to 18-aa sequence that binds to the regulatory subunits (RI or RII) of the kinase. Cellular delivery of peptides to these regions disrupts PKA anchoring and has been used to delineate a physiological role for AKAPs in the facilitation of certain cAMP-responsive events. Here, we describe a bioinformatic approach that yields an RII-selective peptide, called AKAP-in silico (AKAP-IS), that binds RII with a K(d) of 0.4 nM and binds RI with a K(d) of 277 nM. AKAP-IS associates with the type II PKA holoenzyme inside cells and displaces the kinase from natural anchoring sites. Electrophysiological recordings indicate that perfusion of AKAP-IS evokes a more rapid and complete attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents than previously described anchoring inhibitor peptides. Thus, computer-based and peptide array screening approaches have generated a reagent that binds PKA with higher affinity than previously described AKAPs.

Authors
Alto, NM; Soderling, SH; Hoshi, N; Langeberg, LK; Fayos, R; Jennings, PA; Scott, JD
MLA Citation
Alto, NM, Soderling, SH, Hoshi, N, Langeberg, LK, Fayos, R, Jennings, PA, and Scott, JD. "Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring." Proc Natl Acad Sci U S A 100.8 (April 15, 2003): 4445-4450.
PMID
12672969
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
100
Issue
8
Publish Date
2003
Start Page
4445
End Page
4450
DOI
10.1073/pnas.0330734100

Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice.

The Scar/WAVE family of scaffolding proteins organize molecular networks that relay signals from the GTPase Rac to the actin cytoskeleton. The WAVE-1 isoform is a brain-specific protein expressed in variety of areas including the regions of the hippocampus and the Purkinje cells of the cerebellum. Targeted disruption of the WAVE-1 gene generated mice with reduced anxiety, sensorimotor retardation, and deficits in hippocampal-dependent learning and memory. These sensorimotor and cognitive deficits are analogous to the symptoms of patients with 3p-syndrome mental retardation who are haploinsufficient for WRP/MEGAP, a component of the WAVE-1 signaling network. Thus WAVE-1 is required for normal neural functioning.

Authors
Soderling, SH; Langeberg, LK; Soderling, JA; Davee, SM; Simerly, R; Raber, J; Scott, JD
MLA Citation
Soderling, SH, Langeberg, LK, Soderling, JA, Davee, SM, Simerly, R, Raber, J, and Scott, JD. "Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice." Proc Natl Acad Sci U S A 100.4 (February 18, 2003): 1723-1728.
PMID
12578964
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
100
Issue
4
Publish Date
2003
Start Page
1723
End Page
1728
DOI
10.1073/pnas.0438033100

The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling.

WAVE-1, which is also known as Scar, is a scaffolding protein that directs actin reorganization by relaying signals from the GTPase Rac to the Arp2/3 complex. Although the molecular details of WAVE activation by Rac have been described, the mechanisms by which these signals are terminated remain unknown. Here we have used tandem mass spectrometry to identify previously unknown components of the WAVE signalling network including WRP, a Rac-selective GTPase-activating protein. WRP binds directly to WAVE-1 through its Src homology domain 3 and specifically inhibits Rac function in vivo. Thus, we propose that WRP is a binding partner of WAVE-1 that functions as a signal termination factor for Rac.

Authors
Soderling, SH; Binns, KL; Wayman, GA; Davee, SM; Ong, SH; Pawson, T; Scott, JD
MLA Citation
Soderling, SH, Binns, KL, Wayman, GA, Davee, SM, Ong, SH, Pawson, T, and Scott, JD. "The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling." Nat Cell Biol 4.12 (December 2002): 970-975.
PMID
12447388
Source
pubmed
Published In
Nature Cell Biology
Volume
4
Issue
12
Publish Date
2002
Start Page
970
End Page
975
DOI
10.1038/ncb886

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei.

Here we report the cloning, expression, and characterization of a cAMP-specific phosphodiesterase (PDE) from Trypanosoma brucei (TbPDE2B). Using a bioinformatic approach, two different expressed sequence tag clones were identified and used to isolate the complete sequence of two identical PDE genes arranged in tandem. Each gene consists of 2,793 bases that predict a protein of 930 aa with a molecular mass of 103.2 kDa. Two GAF (for cGMP binding and stimulated PDEs, Anabaena adenylyl cyclases, and Escherichia coli FhlA) domains, similar to those contained in many signaling molecules including mammalian PDE2, PDE5, PDE6, PDE10, and PDE11, were located N-terminal to a consensus PDE catalytic domain. The catalytic domain is homologous to the catalytic domain of all 11 mammalian PDEs, the Dictyostelium discoideum RegA, and a probable PDE from Caenorhabditis elegans. It is most similar to the T. brucei PDE2A (89% identity). TbPDE2B has substrate specificity for cAMP with a K(m) of 2.4 microM. cGMP is not hydrolyzed by TbPDE2B nor does this cyclic nucleotide modulate cAMP PDE activity. The nonselective PDE inhibitors 3-isobutyl-1-methylxanthine, papaverine and pentoxifyline are poor inhibitors of TbPDE2B. Similarly, PDE inhibitors selective for the mammalian PDE families 2, 3, 5, and 6 (erythro-9-[3-(2-hydroxynonyl)]-adenine, enoximone, zaprinast, and sildenafil) were also unable to inhibit this enzyme. However, dipyridamole was a reasonably good inhibitor of this enzyme with an IC50 of 27 microM. cAMP plays key roles in cell growth and differentiation in this parasite, and PDEs are responsible for the hydrolysis of this important second messenger. Therefore, parasite PDEs, including this one, have the potential to be attractive targets for selective drug design.

Authors
Rascón, A; Soderling, SH; Schaefer, JB; Beavo, JA
MLA Citation
Rascón, A, Soderling, SH, Schaefer, JB, and Beavo, JA. "Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei." Proc Natl Acad Sci U S A 99.7 (April 2, 2002): 4714-4719.
PMID
11930017
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
99
Issue
7
Publish Date
2002
Start Page
4714
End Page
4719
DOI
10.1073/pnas.002031599

Cloning and characterization of two splice variants of human phosphodiesterase 11A.

Phosphodiesterase 11A (PDE11A) is a recently identified family of cAMP and cGMP hydrolyzing enzymes. Thus far, a single splice variant designated as PDE11A1 has been reported. In this study, we identify and characterize two additional splice variants of PDE11A, PDE11A2 and PDE11A3. The full-length cDNAs are 2,141 bp for PDE11A2 and 2205 bp for PDE11A3. The ORF of PDE11A2 predicts a protein of 576 aa with a molecular mass of 65.8 kDa. The ORF of PDE11A3 predicts a protein of 684 aa with a molecular mass of 78.1 kDa. Comparison of the PDE11A2 sequence with that of PDE11A1 indicates an additional 86 aa at the N terminus of PDE11A2. Part of this sequence extends the potential cGMP binding region (GAF domain) present in PDE11A1. Compared with PDE11A2, PDE11A3 has an additional 108 N-terminal amino acids. Sequence analysis of PDE11A3 indicates the presence of another GAF domain in this region. This diversification of regulatory sequences in the N-terminal region of PDE11A splice variants suggests the interesting possibility of differential regulation of these enzymes. Recombinant PDE11A2 and -A3 proteins expressed in the Baculovirus expression system have the ability to hydrolyze both cAMP and cGMP. The K(m) values for cAMP hydrolysis are 3.3 microM and 5.7 microM for PDE11A2 and PDE11A3, respectively. The K(m) values for cGMP hydrolysis are 3.7 microM and 4.2 microM for PDE11A2 and PDE11A3, respectively. Both PDEs showed a V(max) ratio for cAMP/cGMP of approximately 1.0. PDE11A2 is sensitive to dipyridamole, with an IC(50) of 1.8 microM, and to zaprinast, with an IC(50) of 28 microM. PDE11A3 demonstrated similar pattern of inhibitor sensitivity with IC(50) values of 0.82 and 5 microM for dipyridamole and zaprinast, respectively.

Authors
Hetman, JM; Robas, N; Baxendale, R; Fidock, M; Phillips, SC; Soderling, SH; Beavo, JA
MLA Citation
Hetman, JM, Robas, N, Baxendale, R, Fidock, M, Phillips, SC, Soderling, SH, and Beavo, JA. "Cloning and characterization of two splice variants of human phosphodiesterase 11A." Proc Natl Acad Sci U S A 97.23 (November 7, 2000): 12891-12895.
PMID
11050148
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
97
Issue
23
Publish Date
2000
Start Page
12891
End Page
12895
DOI
10.1073/pnas.200355397

Scar/WAVE-1, a Wiskott-Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold.

WAVE proteins are members of the Wiskott-Aldrich syndrome protein (WASP) family of scaffolding proteins that coordinate actin reorganization by coupling Rho-related small molecular weight GTPases to the mobilization of the Arp2/3 complex. We identified WAVE-1 in a screen for rat brain A kinase-anchoring proteins (AKAPs), which bind to the SH3 domain of the Abelson tyrosine kinase (Abl). Recombinant WAVE-1 interacts with cAMP-dependent protein kinase (PKA) and Abl kinases when expressed in HEK-293 cells, and both enzymes co-purify with endogenous WAVE from brain extracts. Mapping studies have defined binding sites for each kinase. Competition experiments suggest that the PKA-WAVE-1 interaction may be regulated by actin as the kinase binds to a site overlapping a verprolin homology region, which has been shown to interact with actin. Immunocytochemical analyses in Swiss 3T3 fibroblasts suggest that the WAVE-1 kinase scaffold is assembled dynamically as WAVE, PKA and Abl translocate to sites of actin reorganization in response to platelet-derived growth factor treatment. Thus, we propose a previously unrecognized function for WAVE-1 as an actin-associated scaffolding protein that recruits PKA and Abl.

Authors
Westphal, RS; Soderling, SH; Alto, NM; Langeberg, LK; Scott, JD
MLA Citation
Westphal, RS, Soderling, SH, Alto, NM, Langeberg, LK, and Scott, JD. "Scar/WAVE-1, a Wiskott-Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold." EMBO J 19.17 (September 1, 2000): 4589-4600.
PMID
10970852
Source
pubmed
Published In
EMBO Journal
Volume
19
Issue
17
Publish Date
2000
Start Page
4589
End Page
4600
DOI
10.1093/emboj/19.17.4589

Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions.

The past eighteen months have provided much progress in the cyclic nucleotide phosphodiesterase (PDE) field. Six new phosphodiesterase genes have been discovered and characterized. In addition, several new highly specific PDE inhibitors have been developed and approved for clinical use. Finally, new strategies have been employed to determine PDE function in model systems including the use of antisense oligonucleotide and disruption techniques.

Authors
Soderling, SH; Beavo, JA
MLA Citation
Soderling, SH, and Beavo, JA. "Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions." Curr Opin Cell Biol 12.2 (April 2000): 174-179. (Review)
PMID
10712916
Source
pubmed
Published In
Current Opinion in Cell Biology
Volume
12
Issue
2
Publish Date
2000
Start Page
174
End Page
179

Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase.

A member of the phosphodiesterase (PDE)7 family with high affinity and specificity for cAMP has been identified. Based on sequence homologies, we designate this PDE as PDE7B. The full-length cDNA of PDE7B is 2399 bp, and its ORF sequence predicts a protein of 446 amino acids with a molecular mass of 50.1 kDa. Comparison of the predicted protein sequences of PDE7A and PDE7B reveals an identity of 70% in the catalytic domain. Northern blotting indicates that the mRNA of PDE7B is 5.6 kb. It is most highly expressed in pancreas followed by brain, heart, thyroid, skeletal muscle, eye, ovary, submaxillary gland, epididymus, and liver. Recombinant PDE7B protein expressed in a Baculovirus expression system is specific for cAMP with a K(m) of 0.03 microM. Within a series of common PDE inhibitors, it is most potently inhibited by 3-isobutyl-1-methylxanthine with an IC(50) of 2.1 microM. It is also inhibited by papaverine, dipyridamole, and SCH51866 at higher doses. PDE7A and PDE7B exhibit the same general pattern of inhibitor specificity among the several drugs tested. However, differences in IC(50) for some of the drugs suggest that isozyme selective inhibitors can be developed.

Authors
Hetman, JM; Soderling, SH; Glavas, NA; Beavo, JA
MLA Citation
Hetman, JM, Soderling, SH, Glavas, NA, and Beavo, JA. "Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase." Proc Natl Acad Sci U S A 97.1 (January 4, 2000): 472-476.
PMID
10618442
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
97
Issue
1
Publish Date
2000
Start Page
472
End Page
476

Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A

We report here the cloning, expression, and characterization of human PDE11A1, a member of a distinct cyclic nucleotide phosphodiesterase (PDE) family. PDE11A exhibits ≤50% amino acid identity with the catalytic domains of all other PDEs, being most similar to PDE5, and has distinct biochemical properties. The human PDE11A1 cDNA isolated contains a complete open reading frame encoding a 490-amino acid enzyme with a predicted molecular mass of 55,786 Da. At the N terminus PDE11A1 has a single GAF domain homologous to that found in other signaling molecules, including PDE2, PDE5, PDE6, and PDE10, which constitutes a potential allosteric binding site for cGMP or another small ligand. Tissue distribution studies indicate that PDE11A mRNA occurs at highest levels in skeletal muscle, prostate, kidney, liver, pituitary, and salivary glands and testis. PDE11A is expressed as at least three major transcripts of ≃ 10.5, ≃ 8.5, and ≃6.0 kb, thus suggesting the existence of multiple subtypes. This possibility is further supported by the detection of three distinct proteins of ≃ 78, ≃ 65, and ≃ 56 kDa by Western blotting of human tissues for PDE11A isoforms. Recombinant human PDE11A1 hydrolyzes both cGMP and cAMP with K(m) values of 0.52 μM and 1.04 μM, respectively, and similar V(max) values. Therefore, PDE11A represents a dual-substrate PDE that may regulate both cGMP and cAMP under physiological conditions. PDE11A is sensitive to the nonselective PDE inhibitor 3-isobutyl- 1-methylxanthine (IBMX) as well as zaprinast and dipyridamole, inhibitors that are generally considered relatively specific for the cGMP-selective PDEs, with IC50 values of 49.8 μM, 12.0 μM, and 0.37 μM, respectively.

Authors
Fawcett, L; Baxendale, R; Stacey, P; McGrouther, C; Harrow, I; Soderling, S; Hetman, J; Beavo, JA; Phillips, SC
MLA Citation
Fawcett, L, Baxendale, R, Stacey, P, McGrouther, C, Harrow, I, Soderling, S, Hetman, J, Beavo, JA, and Phillips, SC. "Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A." Proceedings of the National Academy of Sciences of the United States of America 97.7 (2000): 3702-3707.
PMID
10725373
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
97
Issue
7
Publish Date
2000
Start Page
3702
End Page
3707
DOI
10.1073/pnas.050585197

Regulation of cAMP and cGMP signaling : new phosphodiesterases and new functions

Authors
SODERLING, SH
MLA Citation
SODERLING, SH. "Regulation of cAMP and cGMP signaling : new phosphodiesterases and new functions." Curr Opin Cell Biol 12 (2000): 174-179.
Source
cinii-english
Published In
Curr Opin Cell Biol
Volume
12
Publish Date
2000
Start Page
174
End Page
179
DOI
10.1016/S0955-0674(99)00073-3

Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A.

We report here the cloning, expression, and characterization of a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE) from mouse. This PDE contains the consensus sequence for a PDE catalytic domain, but shares <50% sequence identity with the catalytic domains of all other known PDEs and, therefore, represents a new PDE gene family, designated PDE10A. The cDNA for PDE10A is 3, 370 nt in length. It includes a full ORF, contains three in-frame stop codons upstream of the first methionine, and is predicted to encode a 779-aa enzyme. At the N terminus PDE10A has two GAF domains homologous to many signaling molecules, including PDE2, PDE5, and PDE6, which likely constitute a low-affinity binding site for cGMP. PDE10A hydrolyzes cAMP with a Km of 0.05 microM and cGMP with a Km of 3 microM. Although PDE10A has a lower Km for cAMP, the Vmax ratio (cGMP/cAMP) is 4.7. RNA distribution studies indicate that PDE10A is expressed at highest levels in testis and brain.

Authors
Soderling, SH; Bayuga, SJ; Beavo, JA
MLA Citation
Soderling, SH, Bayuga, SJ, and Beavo, JA. "Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A." Proc Natl Acad Sci U S A 96.12 (June 8, 1999): 7071-7076.
PMID
10359840
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
96
Issue
12
Publish Date
1999
Start Page
7071
End Page
7076

Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs).

Authors
Juilfs, DM; Soderling, S; Burns, F; Beavo, JA
MLA Citation
Juilfs, DM, Soderling, S, Burns, F, and Beavo, JA. "Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs)." Reviews of physiology, biochemistry and pharmacology 135 (1999): 67-104.
PMID
9932481
Source
scival
Published In
Reviews of physiology, biochemistry and pharmacology
Volume
135
Publish Date
1999
Start Page
67
End Page
104

Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase.

Cyclic nucleotide phosphodiesterases (PDEs) regulate intracellular levels of cAMP and cGMP by hydrolyzing them to their corresponding 5' monophosphates. We report here the cloning and characterization of a novel cAMP-specific PDE from mouse testis. This unique phosphodiesterase contains a catalytic domain that overall shares <40% sequence identity to the catalytic domain of all other known PDEs. Based on this limited homology, this new PDE clearly represents a previously unknown PDE gene family designated as PDE8. The cDNA for PDE8 is 3,678 nucleotides in length and is predicted to encode an 823 amino acid enzyme. The cDNA includes a full ORF as it contains an in-frame stop codon before the start methionine. PDE8 is specific for the hydrolysis of cAMP and has a Km of 0.15 microM. Most common PDE inhibitors are ineffective antagonists of PDE8, including the nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine. Dipyridamole, however, an inhibitor that is generally considered to be relatively specific for the cGMP selective PDEs, does inhibit PDE8 with an IC50 of 4.5 microM. Tissue distribution studies of 22 different mouse tissues indicates that PDE8 has highest expression in testis, followed by eye, liver, skeletal muscle, heart, 7-day embryo, kidney, ovary, and brain in decreasing order. In situ hybridizations in testis, the tissue of highest expression, shows that PDE8 is expressed in the seminiferous epithelium in a stage-specific manner. Highest levels of expression are seen in stages 7-12, with little or no expression in stages 1-6.

Authors
Soderling, SH; Bayuga, SJ; Beavo, JA
MLA Citation
Soderling, SH, Bayuga, SJ, and Beavo, JA. "Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase." Proc Natl Acad Sci U S A 95.15 (July 21, 1998): 8991-8996.
PMID
9671792
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
95
Issue
15
Publish Date
1998
Start Page
8991
End Page
8996

Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases.

We report the cloning, expression, and characterization of a new family of cyclic nucleotide phosphodiesterase (PDE) that has unique kinetic and inhibitor specificities. A clone corresponding to the C terminus of this PDE was initially identified by a bioinformatic approach and used to isolate a cDNA that is likely full-length. This novel PDE, designated as MMPDE9A1, shows highest mRNA expression in kidney with lower levels in liver, lung, and brain. The mRNA size by Northern blot analysis is approximately 2.0 kilobases, and the cDNA encoding PDE9A1 is 1929 base pairs in length. The largest open reading frame predicts a protein of 534 amino acids with a molecular mass of 62,000 Da. When expressed in COS-7 cells, PDE9A1 activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methyl-xanthine or the new selective PDE5 inhibitor, sildenafil, but it is inhibited by the PDE1/5 inhibitor (+)-cis-5,6a, 7,8,9 hyl] phenylmethyl]-5-methyl-cylopent[4,5]imidao[2, 1-b]purin-49(3H)one (SCH51866) with an IC50 of 1.55 microM. This new phosphodiesterase is highly specific for cGMP. Its Km of approximately 0.07 microM for cGMP is the lowest yet reported for a PDE, being at least 40-170 times lower than that of PDE5 and PDE6, respectively.

Authors
Soderling, SH; Bayuga, SJ; Beavo, JA
MLA Citation
Soderling, SH, Bayuga, SJ, and Beavo, JA. "Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases." J Biol Chem 273.25 (June 19, 1998): 15553-15558.
PMID
9624145
Source
pubmed
Published In
The Journal of biological chemistry
Volume
273
Issue
25
Publish Date
1998
Start Page
15553
End Page
15558

Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase

Authors
SODERLING, S
MLA Citation
SODERLING, S. "Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase." Proc Natl Acad Sci USA 95 (1998): 8991-8996.
Source
cinii-english
Published In
Proc Natl Acad Sci USA
Volume
95
Publish Date
1998
Start Page
8991
End Page
8996

Identification and characterization of a novel family of cyclic GMP phosphodiesterases

Authors
Soderling, SH; Bayuga, SJ; Beavo, JA
MLA Citation
Soderling, SH, Bayuga, SJ, and Beavo, JA. "Identification and characterization of a novel family of cyclic GMP phosphodiesterases." NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 358.1 (1998): R663-R663.
Source
wos-lite
Published In
Naunyn-Schmiedeberg's Archives of Pharmacology
Volume
358
Issue
1
Publish Date
1998
Start Page
R663
End Page
R663

Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation.

We have characterized Ca2+/calmodulin-dependent protein kinase IV (CaM kinase IV), expressed using the baculovirus/Sf9 cell system, to assess its potential role in Ca2+-dependent transcriptional regulation. CaM kinase IV was strongly inhibited in vitro by KN-62, a specific CaM kinase inhibitor which suppresses Ca2+-dependent transcription of several genes, so we tested whether CaM kinase IV could stimulate transcription. Co-transfection of COS-1 cells by cDNA for CaM kinase IV gave 3-fold stimulation of a reporter gene expression, whereas co-transfection with CaM kinase II gave no transcriptional stimulation. Since this transcriptional response was mediated by phosphorylation of cAMP responsive element-binding protein (CREB), we determined the kinetics and site specificities of CaM kinases IV and II for phosphorylating CREB in vitro. CaM kinases IV and II and cAMP kinase (protein kinase A) all had similar Km values for CREB (1-5 microns), but the Vmax of CaM kinase IV was 40-fold lower than those of CaM kinase II and protein kinase A. Although all three kinases phosphorylated Ser133 in CREB, CaM kinase II also gave equal phosphorylation of a second site which was not Ser98. The two CREB phosphorylation sites were separately 32P-labeled, and the abilities of protein phosphatases 1, 2A, and 2B (calcineurin) to dephosphorylate them were tested. Our results show that all three phosphatases could dephosphorylate both sites, and calcineurin was a stronger catalyst for dephosphorylating site 1 (Ser133) than for site 2. These results indicate that CaM kinase IV may be important in Ca2+-dependent transcriptional regulation through phosphorylation of Ser133 in CREB. The fact that CaM kinase II phosphorylates another site in addition to Ser133 in CREB raises the possibility that this second phosphorylation site may account for the suppressed phosphorylation site may account for the suppressed ability of CaM kinase II to enhance transcription through the CRE/CREB system. In addition multiple protein phosphatases, including calcineurin, may exert a modulatory effect on transcription depending on which site they dephosphorylate.

Authors
Enslen, H; Sun, P; Brickey, D; Soderling, SH; Klamo, E; Soderling, TR
MLA Citation
Enslen, H, Sun, P, Brickey, D, Soderling, SH, Klamo, E, and Soderling, TR. "Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation." J Biol Chem 269.22 (June 3, 1994): 15520-15527.
PMID
8195196
Source
pubmed
Published In
The Journal of biological chemistry
Volume
269
Issue
22
Publish Date
1994
Start Page
15520
End Page
15527
Show More

Research Areas:

  • 3',5'-Cyclic-AMP Phosphodiesterases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Actin Cytoskeleton
  • Actin-Related Protein 2-3 Complex
  • Actins
  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Avoidance Learning
  • Bacterial Proteins
  • Base Sequence
  • Binding Sites
  • Blotting, Northern
  • Blotting, Southern
  • Brain
  • Brain Chemistry
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Catalysis
  • Cell Compartmentation
  • Cell Line
  • Cell Membrane
  • Cell Movement
  • Cell Polarity
  • Cells, Cultured
  • Cercopithecus aethiops
  • Cerebral Ventricles
  • Chromosomes, Artificial, Bacterial
  • Cloning, Molecular
  • Computational Biology
  • Consensus Sequence
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 7
  • Cytoskeletal Proteins
  • Cytoskeleton
  • DNA, Complementary
  • Databases as Topic
  • Dendritic Spines
  • Dimerization
  • Disease Models, Animal
  • Endocytosis
  • Enzyme Inhibitors
  • Epidermis
  • Exploratory Behavior
  • Expressed Sequence Tags
  • Fertility
  • Fluorescent Dyes
  • GTPase-Activating Proteins
  • Gene Deletion
  • Gene Expression
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Genetic Variation
  • Green Fluorescent Proteins
  • HEK293 Cells
  • HeLa Cells
  • Hippocampus
  • Homeostasis
  • Humans
  • Hydrocephalus
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Indoles
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Keratinocytes
  • Kinetics
  • Learning
  • Lipid Metabolism
  • Liposomes
  • Luminescent Proteins
  • Lymphocyte Activation
  • Macrophages
  • Magnetic Resonance Imaging
  • Male
  • Mass Spectrometry
  • Matrix Attachment Regions
  • Maze Learning
  • Memory
  • Memory Disorders
  • Mental Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microarray Analysis
  • Microfilament Proteins
  • Microscopy, Electron
  • Microscopy, Electron, Scanning
  • Models, Biological
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Weight
  • Motor Activity
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Neuronal Plasticity
  • Neurons
  • Neuropsychological Tests
  • Open Reading Frames
  • Organic Chemicals
  • Penile Erection
  • Peptide Fragments
  • Peptide Library
  • Peptide Mapping
  • Phosphatidylinositols
  • Phosphoproteins
  • Phosphoric Diester Hydrolases
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Photobleaching
  • Potassium Channels
  • Presynaptic Terminals
  • Protein Binding
  • Protein Conformation
  • Protein Engineering
  • Protein Interaction Domains and Motifs
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Proteins
  • Proteomics
  • RNA, Messenger
  • RNA, Untranslated
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A
  • Receptors, Glutamate
  • Recombinant Proteins
  • Restriction Mapping
  • Sensation
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Social Behavior
  • Sperm Motility
  • Sperm Tail
  • Spermatozoa
  • Startle Reaction
  • Stem Cells
  • Subcellular Fractions
  • Substrate Specificity
  • Synapses
  • Synaptic Transmission
  • T-Lymphocytes
  • Testis
  • Thiophenes
  • Time Factors
  • Wiskott-Aldrich Syndrome
  • Wiskott-Aldrich Syndrome Protein Family
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • src Homology Domains