The Insulin Receptor Substrate IRSp53 Links Postsynaptic shank1 to the Small G-Protein cdc42

Soltau, Michaela; Richter, Dietmar; Kreienkamp, Hans‐Jürgen

doi:10.1006/mcne.2002.1201

Cited by 85 publications

(73 citation statements)

References 28 publications

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“…As shown previously, overexpression of IRSp53 in HEK cells induces strong outgrowth of filopodia. IRSp53.1, while strongly present in the cytosol, is also localized to these processes (Soltau et al 2002 and Fig. 3a, left panels).…”

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

confidence: 90%

“…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.…”

mentioning

confidence: 89%

“…Rabbit IRSp53 (rbAnti-IRS) and shank antibodies were used as described (Zitzer et al 1999;Soltau et al 2002); guinea-pig anti-IRS (gpAnti-IRS) was supplied by T. Böckers (University of Münster, Germany). Monoclonal anti-PSD-95 was obtained from Upstate Biotechnology (Lake Placid, NY, USA).…”

Section: Fusion Proteins and Antibodiesmentioning

confidence: 99%

“…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).…”

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confidence: 97%

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

confidence: 90%

mentioning

confidence: 89%

Section: Fusion Proteins and Antibodiesmentioning

confidence: 99%

mentioning

confidence: 97%

See 2 more Smart Citations

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 cdc42 protein controls the formation of actin bundles in membrane ruffling and filopodia formation at the cellular periphery. IRSp53 is also known to localize at postsynaptic density of the central nerve system, which suggests a role in neurite outgrowth (Abbott et al 1999;Soltau et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein

Miyahara

Okamura-Oho²,

Miyashita³

et al. 2003

J Hum Genet

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Insulin receptor tyrosine kinase substrate of 53-kDa protein (IRSp53) is now known to be a key factor in cytoskeleton reorganization. The human IRSp53 was identified as a binding partner with DRPLA protein, a product of the gene responsible for a neurodegenerative disorder, dentatorubral pallidoluysian atrophy, as well as a binding partner with brain-specific angiogenesis inhibitor 1. Previous studies identified at least four isoforms (L-, M-, S-and T-forms) in human, where 511 amino acid residues from the N-terminus were identical, followed by unique sequences of 9-41 amino acid residues. As each isoform had a distinct function, the unique sequences at the C-terminus had a vital role in its function. Here we report that these isoforms were indeed generated by alternative splicing, which was established by experimental and computational studies on human and rodent genomes. Previous biochemical reports suggested that rodents may lack one of the isoforms (L-form). This study solved this issue, as a nucleotide substitution occurred at a splice donor site followed by a large deletion in the rodent genome compared with human, which made the generation of the L-form impossible. This study also revealed overlapping of the IRSp53 and AATK genes coded for by complementary strands.

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Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons

Burette

Park

Weinberg

2014

J of Comparative Neurology

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The 53 kDa insulin receptor substrate protein (IRSp53) is highly enriched in the brain. Despite evidence that links mutations of IRSp53 with autism and other neuropsychiatric problems, the functional significance of this protein remains unclear. We here use light and electron microscopic immunohistochemistry to demonstrate that IRSp53 is expressed throughout the adult rat brain. Labeling concentrated selectively in dendritic spines, where it was associated with the postsynaptic density. Surprisingly, its organization within the PSD of spiny excitatory neurons of neocortex and hippocampus differed from that within spiny inhibitory neurons of neostriatum and cerebellar cortex. The present data support previous suggestions that IRSp53 is involved in postsynaptic signaling, while hinting that its signaling role may differ in different types of neurons.

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The Insulin Receptor Substrate IRSp53 Links Postsynaptic shank1 to the Small G-Protein cdc42

Cited by 85 publications

References 28 publications

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

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

Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein

Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons

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