The Shank Family of Postsynaptic Density Proteins Interacts with and Promotes Synaptic Accumulation of the βPIX Guanine Nucleotide Exchange Factor for Rac1 and Cdc42*

The Shank/ProSAP family of multidomain proteins is known to play an important role in organizing synaptic multiprotein complexes. Here we report a novel interaction between Shank and βPIX, a guanine nucleotide exchange factor for the Rac1 and Cdc42 small GTPases. This interaction is mediated by the PDZ domain of Shank and the C-terminal leucine zipper domain and the PDZ domain-binding motif at the extreme C terminus of βPIX. Shank colocalizes with βPIX at excitatory synaptic sites in cultured neurons. In brain, Shank forms a complex with βPIX and βPIX-associated signaling molecules including p21-associated kinase (PAK), an effector kinase of Rac1/Cdc42. Importantly, overexpression of Shank in cultured neurons promotes synaptic accumulation of βPIX and PAK. Considering the involvement of Rac1 and PAK in spine dynamics, these results suggest that Shank recruits βPIX and PAK to spines for the regulation of postsynaptic structure.

[1]  C. Glover,et al.  Gene expression profiling for hematopoietic cell culture , 2006 .

[2]  Seong-Hwan Rho,et al.  Crystal Structure of GRIP1 PDZ6-Peptide Complex Reveals the Structural Basis for Class II PDZ Target Recognition and PDZ Domain-mediated Multimerization* , 2003, The Journal of Biological Chemistry.

[3]  R. Weinberg,et al.  Interaction between Liprin-α and GIT1 Is Required for AMPA Receptor Targeting , 2003, The Journal of Neuroscience.

[4]  R. Huganir,et al.  Rapid Induction of Dendritic Spine Morphogenesis by trans-Synaptic EphrinB-EphB Receptor Activation of the Rho-GEF Kalirin , 2003, Neuron.

[5]  D. Richter,et al.  The Insulin Receptor Substrate IRSp53 Links Postsynaptic shank1 to the Small G-Protein cdc42 , 2002, Molecular and Cellular Neuroscience.

[6]  J. Bockmann,et al.  ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53 , 2002, Journal of neurochemistry.

[7]  Wei Feng,et al.  PDZ7 of Glutamate Receptor Interacting Protein Binds to Its Target via a Novel Hydrophobic Surface Area* , 2002, The Journal of Biological Chemistry.

[8]  M. Sheng,et al.  Postsynaptic Signaling and Plasticity Mechanisms , 2002, Science.

[9]  T. Boeckers,et al.  ProSAP/Shank proteins – a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease , 2002, Journal of neurochemistry.

[10]  Eunjoon Kim,et al.  Phosphorylation of Stargazin by Protein Kinase A Regulates Its Interaction with PSD-95* , 2002, The Journal of Biological Chemistry.

[11]  R. Weinberg,et al.  Interaction between GRIP and Liprin-α/SYD2 Is Required for AMPA Receptor Targeting , 2002, Neuron.

[12]  M. Ehlers.  Molecular morphogens for dendritic spines , 2002, Trends in Neurosciences.

[13]  R. Vallee,et al.  Dynamin Isoform-specific Interaction with the Shank/ProSAP Scaffolding Proteins of the Postsynaptic Density and Actin Cytoskeleton* , 2001, The Journal of Biological Chemistry.

[14]  L. Lim,et al.  Beta1PIX, the PAK-interacting exchange factor, requires localization via a coiled-coil region to promote microvillus-like structures and membrane ruffles. , 2001, Journal of cell science.

[15]  M. Sheng,et al.  Dentritic spines : structure, dynamics and regulation , 2001, Nature Reviews Neuroscience.

[16]  Richard D Fetter,et al.  Regulation of Postsynaptic Structure and Protein Localization by the Rho-Type Guanine Nucleotide Exchange Factor dPix , 2001, Neuron.

[17]  R. Mains,et al.  Distinct Roles for the Two Rho GDP/GTP Exchange Factor Domains of Kalirin in Regulation of Neurite Growth and Neuronal Morphology , 2001, The Journal of Neuroscience.

[18]  J. Bockmann,et al.  Synaptic Scaffolding Proteins in Rat Brain , 2001, The Journal of Biological Chemistry.

[19]  M. Brown,et al.  Paxillin-ARF GAP signaling and the cytoskeleton. , 2001, Current opinion in cell biology.

[20]  Guosong Liu,et al.  Regulation of Dendritic Spine Morphology and Synaptic Function by Shank and Homer , 2001, Neuron.

[21]  S. Kim,et al.  Leucine zipper-mediated homodimerization of the p21-activated kinase-interacting factor, beta Pix. Implication for a role in cytoskeletal reorganization. , 2001, The Journal of biological chemistry.

[22]  M. Sheng,et al.  Sharpin, a Novel Postsynaptic Density Protein That Directly Interacts with the Shank Family of Proteins , 2001, Molecular and Cellular Neuroscience.

[23]  R. Huganir,et al.  The Neuronal Rho-GEF Kalirin-7 Interacts with PDZ Domain–Containing Proteins and Regulates Dendritic Morphogenesis , 2001, Neuron.

[24]  L. Luo.  RHO GTPASES in neuronal morphogenesis , 2000, Nature Reviews Neuroscience.

[25]  T. Südhof,et al.  The G Protein-coupled Receptor CL1 Interacts Directly with Proteins of the Shank Family* , 2000, The Journal of Biological Chemistry.

[26]  M. Kennedy,et al.  Signal-processing machines at the postsynaptic density. , 2000, Science.

[27]  A. Matus,et al.  Actin-based plasticity in dendritic spines. , 2000, Science.

[28]  E. Gundelfinger,et al.  The Calcium-independent Receptor for α-Latrotoxin from Human and Rodent Brains Interacts with Members of the ProSAP/SSTRIP/Shank Family of Multidomain Proteins* , 2000, The Journal of Biological Chemistry.

[29]  R. Yuste,et al.  Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. , 2000, Cerebral cortex.

[30]  Ann Y. Nakayama,et al.  Small GTPases Rac and Rho in the Maintenance of Dendritic Spines and Branches in Hippocampal Pyramidal Neurons , 2000, The Journal of Neuroscience.

[31]  Sun Hwa Park,et al.  Molecular cloning of neuronally expressed mouse βPix isoforms , 2000 .

[32]  S. Halpain,et al.  Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Huganir,et al.  GRASP-1 A Neuronal RasGEF Associated with the AMPA Receptor/GRIP Complex , 2000, Neuron.

[34]  M. Sheng,et al.  The Shank family of scaffold proteins. , 2000, Journal of cell science.

[35]  R. Mains,et al.  An Isoform of Kalirin, a Brain-specific GDP/GTP Exchange Factor, Is Enriched in the Postsynaptic Density Fraction* , 2000, The Journal of Biological Chemistry.

[36]  D. Richter,et al.  Somatostatin Receptor Interacting Protein Defines a Novel Family of Multidomain Proteins Present in Human and Rodent Brain* , 1999, The Journal of Biological Chemistry.

[37]  Eunjoon Kim,et al.  Characterization of the Shank Family of Synaptic Proteins , 1999, The Journal of Biological Chemistry.

[38]  Y. Hata,et al.  Synamon, a Novel Neuronal Protein Interacting with Synapse-associated Protein 90/Postsynaptic Density-95-associated Protein* , 1999, The Journal of Biological Chemistry.

[39]  S. Bagrodia,et al.  Pak to the future. , 1999, Trends in cell biology.

[40]  T. Boeckers,et al.  Proline-Rich Synapse-Associated Protein-1/Cortactin Binding Protein 1 (ProSAP1/CortBP1) Is a PDZ-Domain Protein Highly Enriched in the Postsynaptic Density , 1999, The Journal of Neuroscience.

[41]  P. Worley,et al.  Coupling of mGluR/Homer and PSD-95 Complexes by the Shank Family of Postsynaptic Density Proteins , 1999, Neuron.

[42]  P. Worley,et al.  Shank, a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/PSD-95/GKAP Complex and Cortactin , 1999, Neuron.

[43]  D. Richter,et al.  Agonist-dependent Interaction of the Rat Somatostatin Receptor Subtype 2 with Cortactin-binding Protein 1* , 1999, The Journal of Biological Chemistry.

[44]  John E. Lisman,et al.  A Role of Actin Filament in Synaptic Transmission and Long-Term Potentiation , 1999, The Journal of Neuroscience.

[45]  R. Lefkowitz,et al.  beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Weed,et al.  Identification of a Novel Cortactin SH3 Domain-Binding Protein and Its Localization to Growth Cones of Cultured Neurons , 1998, Molecular and Cellular Biology.

[47]  L. Van Aelst,et al.  A Novel Regulator of p21-activated Kinases* , 1998, The Journal of Biological Chemistry.

[48]  A. Craig,et al.  Role of Actin in Anchoring Postsynaptic Receptors in Cultured Hippocampal Neurons: Differential Attachment of NMDA versus AMPA Receptors , 1998, The Journal of Neuroscience.

[49]  D. Jo,et al.  Cloning of a SH3 domain-containing proline-rich protein, p85SPR, and its localization in focal adhesion. , 1997, Biochemical and biophysical research communications.

[50]  T. Akiyama,et al.  DAP‐1, a novel protein that interacts with the guanylate kinase‐like domains of hDLG and PSD‐95 , 1997, Genes to cells : devoted to molecular & cellular mechanisms.

[51]  Y. Takai,et al.  SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. , 1997, The Journal of biological chemistry.

[52]  L. Manseau,et al.  A Drosophila gene with predicted rhoGEF, pleckstrin homology and SH3 domains is highly expressed in morphogenic tissues. , 1997, Gene.

[53]  M. Sheng,et al.  GKAP, a Novel Synaptic Protein That Interacts with the Guanylate Kinase-like Domain of the PSD-95/SAP90 Family of Channel Clustering Molecules , 1997, The Journal of cell biology.

[54]  Y. Jan,et al.  Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines , 1996, Nature.

[55]  Y. Jan,et al.  Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases , 1995, Nature.

[56]  M. Kennedy,et al.  The rat brain postsynaptic density fraction contains a homolog of the drosophila discs-large tumor suppressor protein , 1992, Neuron.

[57]  P. Greengard,et al.  Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation , 1983, The Journal of cell biology.

[58]  M. Sheng,et al.  PDZ domains and the organization of supramolecular complexes. , 2001, Annual review of neuroscience.

[59]  G. Banker,et al.  Culturing nerve cells , 1998 .

[60]  X. Q. Chen,et al.  PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. , 1998, Molecular cell.

[61]  Nihon Hassei Seibutsu Gakkai,et al.  Genes to cells , 1996 .

[62]  S. B. Kater,et al.  Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. , 1994, Annual review of neuroscience.