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J Biol Chem, Vol. 273, Issue 12, 6885-6891, March 20, 1998

The Epidermal Growth Factor Receptor Associates with and Recruits Phosphatidylinositol 3-Kinase to the Platelet-derived Growth Factor beta  Receptor

Amyn A. Habib, Thorbergur Högnason, Jane Ren, Kári Stefánsson§, and Rajiv R. Ratan

From the Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115 and § DeCode Genetics, Lynghals 1, Reykjavik, Iceland

Receptor tyrosine kinases are classified into subfamilies, which are believed to function independently, with heterodimerization occurring only within the same subfamily. In this study, we present evidence suggesting a direct interaction between the epidermal growth factor (EGF) receptor (EGFR) and the platelet-derived growth factor beta  (PDGFbeta ) receptor (PDGFbeta R), members of different receptor tyrosine kinase subfamilies. We find that the addition of EGF to COS-7 cells and to human foreskin Hs27 fibroblasts results in a rapid tyrosine phosphorylation of the PDGFbeta R and results in the recruitment of phosphatidylinositol 3-kinase to the PDGFbeta R. In R1hER cells, which overexpress the EGFR, we find ligand-independent tyrosine phosphorylation of the PDGFbeta R and the constitutive binding of a substantial amount of PI-3 kinase activity to it, mimicking the effect of ligand in untransfected cells. In support of the possibility that this may be a direct interaction, we show that the two receptors can be coimmunoprecipitated from untransfected Hs27 fibroblasts and from COS-7 cells. This association can be reconstituted by introducing the two receptors into 293 EBNA cells. The EGFR/PDGFbeta R association is ligand-independent in all cell lines tested. We also demonstrate that the fraction of PDGFbeta R bound to the EGFR in R1hER cells undergoes an EGF-induced mobility shift on Western blots indicative of phosphorylation. Our findings indicate that direct interactions between receptor tyrosine kinases classified under different subfamilies may be more widespread than previously believed.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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