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Src family kinases negatively regulate platelet-derived growth factor alpha receptor-dependent signaling and disease
S Rosenkranz1, Y Ikuno, F L Leong
1The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
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.
Insights
Src family kinases (SFK) and c-Cbl collaborate to degrade the platelet-derived growth factor alpha receptor (alphaPDGFR). This SFK/c-Cbl pathway is crucial for regulating alphaPDGFR signaling and impacts proliferative retinal disease onset.
Area of Science:
- Cellular signaling pathways
- Receptor tyrosine kinase regulation
- Molecular mechanisms of disease
Background:
- Platelet-derived growth factor alpha receptor (alphaPDGFR) signaling is critical for cell growth and proliferation.
- Src family kinases (SFK) and c-Cbl are known regulators of receptor tyrosine kinases.
- The precise interplay between SFKs, c-Cbl, and alphaPDGFR degradation remains incompletely understood.
Purpose of the Study:
- To investigate the role of SFKs in c-Cbl-mediated degradation of alphaPDGFR.
- To determine the functional consequences of altered alphaPDGFR degradation on cellular signaling and disease progression.
- To elucidate the SFK/c-Cbl pathway's involvement in proliferative retinal disease.
Main Methods:
- Utilized a mutant alphaPDGFR unable to engage SFKs (F72/74).
- Employed cells deficient in SFKs.
- Assessed receptor half-life, cellular signaling, S phase entry, and onset of proliferative retinal disease in animal models.
Main Results:
- SFKs were found to contribute to alphaPDGFR degradation.
- Overexpression of c-Cbl reduced receptor half-life only when SFKs were engaged.
- Prolonged receptor half-life enhanced signaling and S phase entry, while accelerated degradation had opposite effects.
- A statistically significant increase in proliferative retinal disease onset was observed with the SFK-non-engaging receptor mutant.
Conclusions:
- SFKs cooperate with c-Cbl to negatively regulate alphaPDGFR.
- The SFK/c-Cbl pathway suppresses alphaPDGFR output, impacting cellular signaling.
- This regulatory mechanism is relevant to the onset and progression of proliferative diseases, particularly in the retina.