Src family kinases negatively regulate platelet-derived growth factor alpha receptor-dependent signaling and disease progression.
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Rosenkranz S, Ikuno Y, Leong FL, Klinghoffer RA, Miyake S, Band H, Kazlauskas A
Src family kinases negatively regulate platelet-derived growth factor alpha receptor-dependent signaling and disease progression.
J Biol Chem. 2000 Mar 31;275(13):9620-7.
- PubMed ID
- 10734113 [ View in PubMed]
- Abstract
We tested the hypothesis that Src family kinases (SFK) contribute to c-Cbl-mediated degradation of the platelet-derived growth factor (PDGF) alpha receptor (alphaPDGFR). Using either a receptor mutant that does not engage SFKs (F72/74), or cells that that lack SFKs, we found that SFKs contributed to degradation of the alphaPDGFR. 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 alphaPDGFR, and that the SFK/c-Cbl suppression of alphaPDGFR output is relevant to the onset and progression of a proliferative disease.