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Cloning and characterization of PHIP, a novel insulin receptor substrate-1 pleckstrin homology domain interacting protein.

Insulin receptor substrate-1 (IRS-1) protein is a major substrate of the insulin receptor tyrosine kinase and is essential for transducing many of the biological effects of insulin including mitogenesis, gene expression, and glucose transport. The N terminus of IRS-1 contains a pleckstrin homology (PH) domain that is critical for recognition and subsequent phosphorylation of IRS-1 by the activated insulin receptor. Here we report the isolation of a novel protein, PHIP (PH-interacting protein), which selectively binds to the PH domain of IRS-1 in vitro and stably associates with IRS-1 in vivo. Importantly, mutants of the IRS-1 PH domain that disrupt the PH fold fail to bind to PHIP. Anti-phosphotyrosine immunoblots of PHIP revealed no discernible insulin receptor-regulated phosphorylation, suggesting that PHIP is not itself a substrate of the insulin receptor. In contrast to full-length PHIP, overexpression of the PH-binding region of PHIP has a pronounced inhibitory effect on insulin-induced IRS-1 tyrosine phosphorylation levels. Furthermore, expression of this dominant-negative PHIP mutant leads to a marked attenuation of insulin-stimulated mitogen-activated protein kinase activity. We conclude that PHIP represents a novel protein ligand of the IRS-1 PH domain that may serve to link IRS-1 to the insulin receptor.

Pubmed ID: 11018022

Authors

  • Farhang-Fallah J
  • Yin X
  • Trentin G
  • Cheng AM
  • Rozakis-Adcock M

Journal

The Journal of biological chemistry

Publication Data

December 22, 2000

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Carrier Proteins
  • Cell Line
  • Cloning, Molecular
  • DNA, Complementary
  • Enzyme Activation
  • Humans
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • Phosphoproteins
  • Phosphorylation
  • Rats
  • Sequence Homology, Amino Acid
  • Tyrosine