Src family kinases negatively regulate platelet-derived growth factor alpha 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) 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.
Rosenkranz
S
S
The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
Ikuno
Y
Y
Leong
F L
FL
Klinghoffer
R A
RA
Miyake
S
S
Band
H
H
Kazlauskas
A
A
D016475:3T3 Cells; D000818:Animals; D004261:DNA Replication; D004195:Disease Models, Animal; D018450:Disease Progression; D006868:Hydrolysis; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011817:Rabbits; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D018630:Vitreoretinopathy, Proliferative / Q000201:enzymology / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D019061:src-Family Kinases; C493849:Cbl protein, mouse