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Originally published In Press as doi:10.1074/jbc.M100928200 on February 5, 2001

J. Biol. Chem., Vol. 276, Issue 18, 15554-15560, May 4, 2001
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Epidermal Growth Factor (EGF) Receptor Kinase-independent Signaling by EGF*

Tushar B. DebDagger , Leon Su§, Lily WongDagger , Ezio Bonvini, Alan Wells||, Michael David§, and Gibbes R. JohnsonDagger **

From the Divisions of Dagger  Therapeutic Proteins and  Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, the § Division of Biology and UCSD Cancer Center, University of California at San Diego, La Jolla, California 92093, and the || Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

The ErbB family of receptors, which includes the epidermal growth factor receptor (EGFR), ErbB2, ErbB3, and ErbB4, mediate signaling by EGF-like polypeptides. To better understand the role of the EGFR tyrosine kinase, we analyzed signaling by a kinase-inactive EGFR (K721M) in ErbB-devoid 32D cells. K721M alone exhibited no detectable signaling capacity, whereas coexpression of K721M with ErbB2, but not ErbB3 or ErbB4, resulted in EGF-dependent mitogen-activated protein kinase (MAPK) activation. The kinase activity, but not tyrosine phosphorylation, of ErbB2 was required for EGF-induced MAPK activation. The presence of tyrosine phosphorylation sites in K721M was not a requisite for signaling, indicating that transphosphorylation of K721M by ErbB2 was not an essential mechanism of receptor activation. Conversely, the mutated kinase domain of K721M (residues 648-973) and tyrosine phosphorylation of at least one of the receptors were necessary. EGF was found to activate the pro-survival protein kinase Akt in stable cell lines expressing K721M and ErbB2 but, unlike cells expressing wild-type EGFR, was incapable of activating signal transducers and activators of transcription (STAT) or driving cell proliferation. These results demonstrate that EGFR-ErbB2 oligomers are potent activators of MAPK and Akt, and this signaling does not require EGFR kinase activity.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bldg. 29A, Rm. 3B-16, 8800 Rockville Pike, Bethesda, MD 20892. Tel.: 301-827-1770; Fax: 301-480-3256; E-mail: Johnsong@cber.fda.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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