Synamon, a Novel Neuronal Protein Interacting with Synapse-associated Protein 90/Postsynaptic Density-95-associated Protein

Yao, Ikuko; Hata, Yoshinobu; Hirao, Kazuyo; Deguchi, Maki; Ide, Nobuyuki; Takeuchi, Masami; Takai, Yoshimi

doi:10.1074/jbc.274.39.27463

Cited by 90 publications

(91 citation statements)

References 20 publications

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“…Shank and ␤PIX Colocalize at Synaptic Sites in Cultured Neurons-Shank proteins are mainly localized to synaptic sites in cultured neurons (10,11). However, little is known about the subcellular distribution pattern of ␤PIX.…”

Section: Spatiotemporal Expression Of ␤Pix and Its Association Withmentioning

confidence: 99%

“…The C-terminal SAM domain mediates multimerization of Shank proteins (10). There are several splice variants of Shank with alternative translational start and stop codons, suggesting that the Shank protein interactions are regulated by alternative splicing (11,12,21,22).Functionally, Shank is involved in the morphogenesis of dendritic spines (3, 23). Overexpression of Shank proteins promotes the maturation of spines in cultured neurons (24).…”

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confidence: 99%

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

Park

Choi

et al. 2003

Journal of Biological Chemistry

157

160

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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 ␤PIX, 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 ␤PIX. Shank colocalizes with ␤PIX at excitatory synaptic sites in cultured neurons. In brain, Shank forms a complex with ␤PIX and ␤PIX-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 ␤PIX and PAK. Considering the involvement of Rac1 and PAK in spine dynamics, these results suggest that Shank recruits ␤PIX and PAK to spines for the regulation of postsynaptic structure.Dendritic spines are actin-rich morphological specializations in neurons that mediate most excitatory synaptic transmission (1-3). The postsynaptic density (PSD) 1 is a microscopic structure within dendritic spines that is associated with the postsynaptic membrane and contains a variety of scaffolding and signaling proteins (4, 5).The Shank/ProSAP/SSTRIP family of multidomain proteins (Shank1, Shank2, and Shank3) plays important roles in organizing the PSD (6, 7). Shank is a relatively large protein (ϳ200 kDa) and contains various protein interaction domains including, from the N terminus, ankyrin repeats, an SH3 domain, a PDZ domain, a long (Ͼ1000 aa residues) proline-rich region and a SAM domain. The ankyrin repeats interact with ␣-fodrin, an actin-regulating protein, and Sharpin, a protein implicated in Shank multimerization (8, 9). The Shank PDZ domain interacts with the GKAP/SAPAP family of synaptic scaffold proteins and various membrane proteins including the calciumindependent receptor for latrotoxin, somatostatin receptors, and metabotropic glutamate receptors (10 -16). The long proline-rich region of Shank associates with IRSp53 (an insulin receptor tyrosine kinase substrate protein), Homer (an immediate early gene product that binds the group I metabotropic receptors and inositol 1,4,5-trisphosphate receptors), dynamin (a GTPase that regulates endocytosis), and cortactin (a regulator of the cortical actin cytoskeleton) (16 -20). The C-terminal SAM domain mediates multimerization of Shank proteins (10). There are several splice variants of Shank with alternative translational start and stop codons, suggesting that the Shank protein interactions are regulated by alternative splicing (11,12,21,22).Functionally, Shank is involved in the morphogenesis of dendritic spines (3, 23). Overexpression of Shank proteins promotes the maturation of spines in cultured neurons (24). The enhanced spine maturation by Shank requires the interaction of Shank with Homer, a protein that binds to metabotropic glutamate receptors and inositol 1,4,5-trisphosphate receptors (16). In addition, expression of ...

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Section: Spatiotemporal Expression Of ␤Pix and Its Association Withmentioning

confidence: 99%

mentioning

confidence: 99%

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

Park

Choi

et al. 2003

Journal of Biological Chemistry

157

160

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“…The weak coprecipitation of PSD-95 by shank1 in the absence of IRSp53 may be explained by the presence of endogenous IRSp53.1, or SAPAP/GKAP in HEK cells. SAPAP/GKAP proteins constitute a second class of proteins, which bridge shank and PSD-95 (Boeckers et al 1999;Naisbitt et al 1999;Yao et al 1999). To further show that all three proteins exist in one complex in the rodent brain, we precipitated PSD-95 from solubilized mouse brain using the NMDA-receptor C-terminal peptide immobilized on NHS sepharose.…”

Section: The C-terminus Of Irsp53 Interacts With Pdz2 Of Psd-95mentioning

confidence: 99%

“…The function of the PSD appears to be to physically link postsynaptic receptors to signalling molecules, and to provide stable attachment of the receptors to the actin-based cytoskeleton of the dendritic spine. Shank proteins (shank1-3, also known as SSTRIP, ProSAP, synamon or CortBP) constitute another group of postsynaptic scaffolding molecules which link transmitter receptors (Kreienkamp et al 2000;Naisbitt et al 1999;Yao et al 1999;Zitzer et al 1999) to actin binding proteins (Du et al 1998;Boeckers et al 2001;Okamoto et al 2001). Overexpression of shank1 in neurones leads to enhanced maturation of dendritic spines .…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD‐95

Soltau

Berhörster

Kindler

et al. 2004

Journal of Neurochemistry

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The insulin receptor substrate of 53 kDa (IRSp53) is a target of the small GTPase cdc42 which is strongly enriched in the postsynaptic density of excitatory synapses. IRSp53 interacts with the postsynaptic shank1 scaffolding molecule in a cdc42 regulated manner. The functional significance of the cdc42/ IRSp53 pathway in postsynaptic sites is however, unclear. The generation of excitatory synapses in the central nervous system requires a complex assembly process in which elements of the postsynaptic receptor apparatus are assembled at postsynaptic sites on dendrites. In many cases, glutamatergic synapses are localized on the heads of dendritic spines (Harris and Kater 1994; see review by Hering and Sheng 2001). During maturation postsynaptic proteins accumulate at the synapse, as exemplified in several studies by the appearance of clusters of the postsynaptic marker PSD-95 (Friedman et al. 2000;Okabe et al. 2001). Via its PDZ domains, PSD-95 is one of the major anchoring proteins for postsynaptic transmitter receptors and ion channels (Kim et al. 1995;Kornau et al. 1995). Through an intricate network of protein interactions, a large protein complex of up to 100 proteins is assembled at the spine heads around the PSD-95/transmitter receptor complex (Husi et al. 2000;Walikonis et al. 2000;Li et al. 2004) which has been termed the postsynaptic density (PSD). The function of the PSD appears to be to physically link postsynaptic receptors to signalling molecules, and to provide stable attachment of the receptors to the actin-based cytoskeleton of the dendritic spine. Shank proteins (shank1-3, also known as SSTRIP, ProSAP, synamon or CortBP) constitute another group of postsynaptic scaffolding molecules which link transmitter receptors (Kreienkamp et al. 2000;Naisbitt et al. 1999;Yao et al. 1999;Zitzer et al. 1999) to actin binding proteins (Du et al. 1998;Boeckers et al. 2001;Okamoto et al. 2001). Overexpression of shank1 in neurones leads to enhanced maturation of dendritic spines . We and others have recently identified IRSp53 as an interaction partner for shank1 (Bockman et al. 2002;Soltau et al. 2002). A proline-rich region of shank1 binds to the SH3 domain of IRSp53 in a cdc42-regulated manner (Soltau et al. 2002). These data suggested that shank1 might be an effector molecule of cdc42 in an undefined regulatory pathway. Here, we show that IRSp53, via binding to a PDZ domain of the PSD-95 molecule, mediates the formation of a triple complex consisting of shank1 and PSD-95. Our data suggest that one result of cdc42/IRSp53 signalling is the regulated assembly of a macromolecular complex between shank and PSD-95 proteins.Received January 14, 2004; revised manuscript received March 19, 2004; accepted March 23, 2004. Address correspondence and reprint requests to Hans-Jürgen Kreienkamp, Institut für Zellbiochemie und klinische Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: kreienkamp@uke.uni-hamburg.deAbbreviations used: IRSp53, insulin receptor su...

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“…SAPAP may link components of the PSD to Triton X-100-insoluble structures. Recently, two proteins, Shank 1a/synamon and nArgBP2, have been identi®ed as SAPAP-interacting proteins (Kawabe et al 1999;Yao et al 1999b). Both of them are indirectly associated with the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Association of synapse‐associated protein 90/ postsynaptic density‐95‐associated protein (SAPAP) with neurofilaments

et al. 2000

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Background: Synapse-associated protein (SAP) 90/Postsynaptic density (PSD)-95-associated protein (SAPAP) (also called Guanylate kinase-associated protein/hDLG-associated protein) interacts with the guanylate kinase domains of PSD-95 and synaptic scaffolding molecule (S-SCAM) via the middle region containing 5 repeats of 14 amino acids. SAPAP also binds the recently identi®ed proteins, nArgBP2 and synamon (also called Shank 1a), via the proline-rich region and the C-terminus, respectively. SAPAP is highly enriched in the Triton X-100-insoluble PSD fraction, and recruits PSD-95 into the Triton X-100-insoluble fraction in transfected cells. We have further characterized here the Triton X-100-insolubility of SAPAP and tried to identify the Triton X-100-insoluble structures which SAPAP interacts with.

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Synamon, a Novel Neuronal Protein Interacting with Synapse-associated Protein 90/Postsynaptic Density-95-associated Protein

Cited by 90 publications

References 20 publications

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

Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD‐95

Association of synapse‐associated protein 90/ postsynaptic density‐95‐associated protein (SAPAP) with neurofilaments

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