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PMID:7559478

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Citation

He, W, O'Neill, TJ and Gustafson, TA (1995) Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non-SH2 domains. J. Biol. Chem. 270:23258-62

Abstract

Insulin receptor substrate 1 (IRS-1) and src homology and collagen protein (SHC) are signaling proteins which are rapidly phosphorylated on tyrosines after insulin receptor (IR) activation. We have recently shown that both SHC and IRS-1 interact with the tyrosine-phosphorylated NPEY motif of the IR and insulin-like growth factor I receptor via non-SH2 domains (Gustafson, T. A., He, W., Craparo, A., Schaub, C. D., and O'Neill, T. J. (1995) Mol. Cell. Biol. 15, 2500-2508; O'Neill, T. J., Craparo, A., and Gustafson, T. A. (1994) Mol. Cell. Biol. 14, 6433-6442; Craparo, A., O'Neill, T. J., and Gustafson, T. A. (1995) J. Biol. Chem. 270, 15639-15643). In this study we characterize these interactions by examining the effects of 18 amino acid substitutions within and around the IR NPEY motif upon interaction with SHC and IRS-1. We confirm that Tyr-960 within the NPEY motif of the IR is essential for both IRS-1 and SHC interaction and that Asn-957 and Pro-958 are essential for IRS-1 interaction and important but not critical for SHC interaction. Additional mutations surrounding the NPEY motif revealed completely distinct patterns of interaction for SHC and IRS-1. Specifically, mutation of Leu-952 or Tyr-953 (at positions -7 and -8 from Tyr-960) markedly reduced IRS-1 interaction but had no effect upon SHC interaction. Likewise, mutation of Ala-963 (+3) reduced IRS-1 but not SHC interaction. Conversely, substitution of Leu-961 (+1) with either Ala or Arg reduced SHC interaction by 70 and 90%, respectively, yet had no effect upon interaction with IRS-1. Our data show that the sequences within and surrounding the NPEY contribute differentially to either SHC or IRS-1 recognition. Our findings suggest mechanisms by which the differential interaction of known receptors with IRS-1 and SHC may be mediated.

Links

PubMed

Keywords

Amino Acid Sequence; Binding Sites; Insulin Receptor Substrate Proteins; Models, Biological; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphoproteins/genetics; Phosphoproteins/metabolism; Phosphorylation; Protein Sorting Signals/genetics; Protein Sorting Signals/metabolism; Proto-Oncogene Proteins pp60(c-src)/genetics; Proto-Oncogene Proteins pp60(c-src)/metabolism; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; beta-Galactosidase/genetics; beta-Galactosidase/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SHC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9PVZ4

F

Seeded From UniProt

complete

HUMAN:IRS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9PVZ4

F

Seeded From UniProt

complete

XENLA:INSR

enables

GO:0051425: PTB domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35568

F

Seeded From UniProt

complete

XENLA:INSR

enables

GO:0051425: PTB domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29353

F

Seeded From UniProt

complete

HUMAN:INSR

enables

GO:0051425: PTB domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29353

F

Seeded From UniProt

complete

HUMAN:INSR

enables

GO:0043560: insulin receptor substrate binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35568

F

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06213

P

Seeded From UniProt

complete


See also

References

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