Src family kinases negatively regulate platelet-derived growth factor α receptor-dependent signaling and disease progression

We tested the hypothesis that Src family kinases (SFK) contribute to c- Cbl-mediated degradation of the platelet-derived growth factor (PDGF) α receptor (αPDGFR). Using either a receptor mutant that does not engage SFKs (F72174), or cells that that lack SFKs, we found that SFKs contributed to degradation of the αPDGFR. Overexpression of c-Cbl also reduced the receptor half-life, but only if the receptor was able to engage SFKs. In cultured cells, prolonging the half-life of the receptor correlated with enhanced signaling and more efficient S phase entry, whereas accelerating receptor degradation had the opposite effect. Consistent with these tissue culture findings, there was a statistically significant increase in the onset of a proliferative retinal disease when animals were injected with cells expressing the F72/74 receptor, as compared with cells expressing the WT receptor. Our findings suggest that SFKs cooperate with c-Cbl to negatively regulate the αPDGFR, and that the SFK/c-Cbl suppression of αPDGFR output is relevant to the onset and progression of a proliferative disease.