Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.

Abstract:

:Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.

journal_name

Nature

journal_title

Nature

authors

Sun XJ,Rothenberg P,Kahn CR,Backer JM,Araki E,Wilden PA,Cahill DA,Goldstein BJ,White MF

doi

10.1038/352073a0

keywords:

subject

Has Abstract

pub_date

1991-07-04 00:00:00

pages

73-7

issue

6330

eissn

0028-0836

issn

1476-4687

journal_volume

352

pub_type

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