STAT Activation by Epidermal Growth Factor (EGF) and Amphiregulin: REQUIREMENT FOR THE EGF RECEPTOR KINASE BUT NOT FOR TYROSINE PHOSPHORYLATION SITES OR JAK1

Michael David,Lily Wong,Richard Flavell,Stewart A Thompson,Alan Wells,Andrew C Larner,Gibbes R Johnson

doi:10.1074/jbc.271.16.9185

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.

Highlights

From the ‡Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, ¶Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510, ʈDepartment of Protein Chemistry and Biophysics, Berlex Biosciences, Richmond, California 94804, and **Department of Pathology, University of Alabama at Birmingham and Veterans Administration Medical Center, Birmingham, Alabama 35294
These results provide the first evidence that (i) epidermal growth factor (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
We wanted to investigate whether AR, another growth factor known to signal through the EGF receptor [21], activates STAT proteins in a manner similar to EGF

Summary

Introduction

From the ‡Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, ¶Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510, ʈDepartment of Protein Chemistry and Biophysics, Berlex Biosciences, Richmond, California 94804, and **Department of Pathology, University of Alabama at Birmingham and Veterans Administration Medical Center, Birmingham, Alabama 35294. Jak1 Is Not Required for EGF Receptor-mediated Activation of STATs—It has been previously shown that EGF can stimulate tyrosine phosphorylation of STAT 1, 3, and 5 such that they can bind to the IFN␥-activated sequence-like enhancers (6 – 8).

Results

Conclusion