G Subunits Mediate Mitogen-activated Protein Kinase Activation by the Tyrosine Kinase Insulin-like Growth Factor 1 Receptor

doi:10.1074/jbc.270.28.16495

G Subunits Mediate Mitogen-activated Protein Kinase Activation by the Tyrosine Kinase Insulin-like Growth Factor 1 Receptor (*)

From the (1)From The Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

^¶ To whom correspondence and reprint requests should be addressed. Tel.: 919-684-2974; Fax: 919-684-8875.

Abstract

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stimulation of mitogen-activated protein (MAP) kinase via the IGF1 receptor and the Gⁱ-coupled receptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expression of a specific G subunit-binding peptide. The IGF1, LPA, and EGF receptor-mediated signals are all sensitive to inhibitors of tyrosine protein kinases, require p21 activation, and are independent of protein kinase C. These data suggest that some tyrosine kinase growth factor receptors (e.g. IGF1 receptor) and classical G protein-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G subunits derived from pertussis toxin-sensitive G proteins.

Footnotes

↵§ Recipient of a postdoctoral award from the Alberta Heritage Foundation for Medical Research.
↵* This work was supported in part by National Institutes of Health Grant HL 16037. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

MAP

mitogen-activated protein

IGF1

insulin-like growth factor 1

EGF

epidermal growth factor

LPA

lysophosphatidic acid

PT

pertussis toxin

IRS-1

insulin receptor substrate 1

DMEM

Dulbecco's modified Eagle's medium

PMA

phorbol 12-myristate 13-acetate

MBP

myelin basic protein

PKC

protein kinase C

PI

phosphatidylinositol.
↵² T. van Biesen and R. J. Lefkowitz, unpublished observation.