Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression.

Abstract:

:Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation. Strikingly, replacement of leucine973 in the juxtamembrane region of IR to phenylalanine, which is present in IGF1R, mimics many of these signalling and gene expression responses. Overall, we show that the distinct activities of the closely related IR and IGF1R are mediated by their intracellular juxtamembrane region and substrate binding to this region.

journal_name

Nat Commun

journal_title

Nature communications

authors

Cai W,Sakaguchi M,Kleinridders A,Gonzalez-Del Pino G,Dreyfuss JM,O'Neill BT,Ramirez AK,Pan H,Winnay JN,Boucher J,Eck MJ,Kahn CR

doi

10.1038/ncomms14892

subject

Has Abstract

pub_date

2017-03-27 00:00:00

pages

14892

issn

2041-1723

pii

ncomms14892

journal_volume

8

pub_type

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