STAT Activation by Epidermal Growth Factor (EGF) and Amphiregulin

doi:10.1074/jbc.271.16.9185

STAT Activation by Epidermal Growth Factor (EGF) and Amphiregulin

REQUIREMENT FOR THE EGF RECEPTOR KINASE BUT NOT FOR TYROSINE PHOSPHORYLATION SITES OR JAK1 (*)

From the (1)Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,
(2)Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510,
(3)Department of Protein Chemistry and Biophysics, Berlex Biosciences, Richmond, California 94804, and
(4)Department of Pathology, University of Alabama at Birmingham and Veterans Administration Medical Center, Birmingham, Alabama 35294

^§To whom correspondence may be addressed:
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bldg. 29A, Rm. 2B06, 8800 Rockville Pike, Bethesda, MD 20892.
Tel.: 301-496-9012; Fax: 301-402-1659.

Abstract

The epidermal growth factor (EGF) receptor activates several signaling cascades in response to the ligands EGF and amphiregulin (AR). One of these signaling events involves the tyrosine phosphorylation of STATs (signal transducers and activators of transcription), a process believed to require the activation of a tyrosine kinase of the JAK family. In this report we demonstrate that EGF- and AR-induced STAT activation requires the intrinsic kinase activity of the receptor but not the presence of Jak1. We show that both wild type (WT) and truncated EGF receptors lacking all autophosphorylation sites activate STAT 1, 3, and 5 in response to either EGF or AR. Furthermore, relative to cells expressing WT receptor, ligand-induced tyrosine phosphorylation of the STATs was enhanced in cells expressing only the truncated receptor. These results provide the first evidence that (i) EGF receptor-mediated STAT activation occurs in a Jak1-independent manner, (ii) the intrinsic tyrosine kinase activity of the receptor is essential for STAT activation, and (iii) tyrosine phosphorylation sites within the EGF receptor are not required for STAT activation.

Footnotes

↵* 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:

EGF

epidermal growth factor

AR

amphiregulin

IFN

-interferon

STAT

signal transducer and activator of transcription

EMSA

electrophoretic mobility shift assay

SIE

c-sis inducible element

WT

wild type

SH2

Src homology 2.
↵²S. A. Thompson, A. Harris, D. Hoang, M. Ferrer, and G. R. Johnson, manuscript in preparation.
↵³S. Rani, S. Shinagawa, and G. R. Johnson, manuscript in preparation.
- Received November 28, 1995.
- Revision received February 8, 1996.