A Role for Src in Signal Relay by the Platelet-derived Growth Factor α Receptor

Previous studies have shown that Src is required for platelet-derived growth factor (PDGF)-dependent cell cycle progression in fibroblasts. Since fibroblasts usually express both PDGF receptors (PDGFRs), these findings suggested that Src was mandatory for signal relay by both the α and βPDGFRs. In this study, we have focused on the role of Src in signal relay by the αPDGFR. In response to stimulation with PDGF-AA, which selectively engages the αPDGFR, Src family members (Src) associated with the αPDGFR and Src kinase were activated. A mutant receptor, in which tyrosines 572 and 574 were replaced with phenylalanine (F72/74), failed to efficiently associate with Src or activate Src. The wild type (WT) and F72/74 receptors induced the expression of c-myc and c-fos to comparable levels. Furthermore, an equivalent extent of PDGF-dependent soft agar growth was observed in cells expressing the WT or the F72/74 αPDGFR. Comparing the ability of these two receptors to initiate tyrosine phosphorylation of signaling molecules indicated that both receptors mediated phosphorylation of the receptor itself, phospholipase Cγ 1, and SHP-2 to similar levels. In contrast, the F72/74 receptor triggered phosphorylation of Shc to 1 and 20% of the WT levels for the 55- and 46-kDa Shc isoforms, respectively. These findings indicate that after exposure of cells to PDGF-AA, Src stably associates with the αPDGFR, and Src activity is increased. Furthermore, Src is required for the PDGF-dependent phosphorylation of signaling molecules such as Shc. Finally, activation of Src during the G0/G1 transition does not appear to be required for latter cell cycle events such as induction of c-myc or cell proliferation.