THE EPIDERMAL GROWTH-FACTOR RECEPTOR ASSOCIATES WITH AND RECRUITS PHOSPHATIDYLINOSITOL 3-KINASE TO THE PLATELET-DERIVED GROWTH-FACTOR-BETA RECEPTOR

Receptor tyrosine kinases are classified into subfamilies, which are b elieved to function independently, with heterodimerization occurring o nly within the same subfamily, In this study, we present evidence sugg esting a direct interaction between the epidermal growth factor (EGF) receptor (EGFR) and the platelet-derived growth factor beta (PDGF beta ) receptor (PDGF beta R), members of different receptor tyrosine kinas e subfamilies, We find that the addition of EGF to COS-7 cells and to human foreskin Hs27 fibroblasts results in a rapid tyrosine phosphoryl ation of the PDGF beta R and results in the recruitment of phosphatidy linositol 3-kinase to the PDGF beta R. In R1hER cells, which overexpre ss the EGFR, we find ligand-independent tyrosine phosphorylation of th e PDGF beta R and the constitutive binding of a substantial amount of PI-3 kinase activity to it, mimicking the effect of Ligand in untransf ected cells, In support of the possibility that this may be a direct i nteraction, we show that the two receptors can be coimmunoprecipitated from untransfected Hs27 fibroblasts and from COS-7 cells, This associ ation can be reconstituted by introducing the two receptors into 293 E BNA cells, The EGFR/PDGF beta R association is ligand-independent in a ll cell lines tested, We also demonstrate that the fraction of PDGF be ta R bound to the EGFR in R1hER cells undergoes an EGF-induced mobilit y shift on Western blots indicative of phosphorylation, Our findings i ndicate that direct interactions between receptor tyrosine kinases cla ssified under different subfamilies may be more widespread than previo usly believed.