Title

Ligand-Independent Phosphorylation Of Y869 (Y845) Links Mutant Egfr Signaling To Stat-Mediated Gene Expression

Keywords

EGFR; Lung cancer; Phosphorylation; Src; STAT

Abstract

Activating mutants of EGFR have been identified in a subset of non-small-cell lung cancers. To investigate mutant-driven signaling, we focused on Y869, a residue in the same activation loop where the L858R and L861Q mutations are located. We observed ligand-independent phosphorylation of Y869 in 32D cells EGFRL858R and EGFRL861Q. The EGFR tyrosine kinase inhibitor (TKI) erlotinib inhibited Y869 P-EGFR in intact cells as well as in a cell-free kinase reaction. Expression of kinase domain of EGFRL858R and EGFRL861Q exhibited auto-phosphorylation of Y869; this was inhibited by EGFR TKIs but not by Src kinase inhibitor. P-Y859 of EGFR-mediated downstream component, STAT5, was also analyzed. Y694 P-STAT5 was eliminated by erlotinib treatment. Analysis of immune-complexes showed constitutive association of mutant EGFRs with STAT5 and Src which was unaffected by erlotinib or PP1. On the other hand, 32D-EGFRWT exhibited constitutive STAT5 phosphorylation and association of EGFR with JAK2. In these cells, a JAK2 inhibitor abrogated P-STAT5 whereas mutant EGFRs did not associate with JAK2. Expression of c-myc was regulated by EGFR/STAT5 signaling in cells expressing EGFRL858R and EGFRL861Q. Our results suggest that ligand-independent and Src activity-independent phosphorylation of Y869 in mutant EGFR regulates STAT5 activation and c-myc expression. © 2007 Elsevier Inc. All rights reserved.

Publication Date

1-15-2008

Publication Title

Experimental Cell Research

Volume

314

Issue

2

Number of Pages

413-419

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.yexcr.2007.09.002

Socpus ID

36749054018 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/36749054018

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