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PMID:7537849

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Citation

Gustafson, TA, He, W, Craparo, A, Schaub, CD and O'Neill, TJ (1995) Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain. Mol. Cell. Biol. 15:2500-8

Abstract

The SHC proteins have been implicated in insulin receptor (IR) signaling. In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR. The interaction is mediated by SHC amino acids 1 to 238 and is therefore independent of the Src homology 2 domain. The interaction is dependent upon IR autophosphorylation, since the interaction is eliminated by mutation of the IR ATP-binding site. In addition, mutational analysis of the Asn-Pro-Glu-Tyr (NPEY) motif within the juxtamembrane domain of the IR showed the importance of the Asn, Pro, and Tyr residues to both SHC and IR substrate 1 (IRS-1) binding. We conclude that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction. This interaction is highly reminiscent of that of IRS-1 with the IR, and we show that the SHC IR-binding domain can substitute for that of IRS-1 in yeast and COS cells. We identify a homologous region within the IR-binding domains of SHC and IRS-1, which we term the SAIN (SHC and IRS-1 NPXY-binding) domain, which may explain the basis of these interactions. The SAIN domain appears to represent a novel motif which is able to interact with autophosphorylated receptors such as the IR.

Links

PubMed PMC230480

Keywords

Amino Acid Sequence; Animals; Binding Sites/genetics; Cell Line; Cloning, Molecular; Humans; Insulin Receptor Substrate Proteins; Models, Biological; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphoproteins/metabolism; Phosphotyrosine; Proteins/genetics; Proteins/metabolism; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Saccharomyces cerevisiae/genetics; Sequence Homology, Amino Acid; Signal Transduction; Tyrosine/analogs & derivatives; Tyrosine/metabolism

Significance

Annotations

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

HUMAN:INSR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29353

F

Seeded From UniProt

complete

XENLA:INSR

involved_in

GO:0046777: protein autophosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INSR

involved_in

GO:0046777: protein autophosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

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:INSR

enables

GO:0043548: phosphatidylinositol 3-kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P27986

F

Seeded From UniProt

complete

HUMAN:INSR

enables

GO:0004713: protein tyrosine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SHC1

enables

GO:0005158: insulin receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06213

F

Seeded From UniProt

complete

HUMAN:IRS1

enables

GO:0005158: insulin receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06213

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

HUMAN:P85A

enables

GO:0005158: insulin receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06213

F

Seeded From UniProt

complete


See also

References

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