Receptor heterodimerization: Essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation

Previous studies showed that the epidermal growth factor receptor (EGFR) ca n be transactivated by platelet-derived growth factor (PDGF) stimulation an d that EGFR transactivation is required for PDGF-stimulated cell migration. To investigate the mechanism for cross talk between the PDGF beta receptor (PDGF betaR) and the EGFR, we stimulated rat aortic vascular smooth muscle cells (VSMC) with 20 ng of PDGF/ml. Transactivation of the EGFR, defined b y receptor tyrosine phosphorylation, occurred with the same time course as PDGF betaR activation. Basal formation of PDGF betaR-EGFR heterodimers was shown by coimmunoprecipitation studies, and interestingly, disruption of th is receptor heterodimer abolished EGFR transactivation. Breakdown of the he terodimer was observed when VSMC were pretreated with antioxidants or with a Src family kinase inhibitor. Disruption of heterodimers decreased ERK1 an d ERK2 activation by PDGF. Although PDGF-induced PDGF betaR activation was abolished after pretreatment with 1 muM AG1295 (a specific PDGF receptor ki nase inhibitor), EGFR transactivation was still observed, indicating that P DGF betaR kinase activity is not required. In conclusion, our data demonstr ate that the PDGF betaR and the EGFR form PDGF betaR-EGFR heterodimers basa lly, and we suggest that heterodimers represent a novel signaling complex w hich plays an important role in PDGF signal transduction.