The epidermal growth factor receptor associates with and recruits phosphatidylinositol 3-kinase to the platelet-derived growth factor β receptor

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 (PDGF beta) receptor (PDGF beta 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 PDGF beta R and results in the recruitment of phosphatidylinositol 3-kinase to the PDGF beta R. In R1hER cells, which overexpress the EGFR, we find ligand-independent tyrosine phosphorylation of the PDGF beta 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/PDGF beta R association is ligand-independent in all cell lines tested, We also demonstrate that the fraction of PDGF beta 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.