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J Biol Chem, Vol. 275, Issue 13, 9620-9627, March 31, 2000
From We tested the hypothesis that Src family kinases
(SFK) contribute to c-Cbl-mediated degradation of the platelet-derived
growth factor (PDGF)
Src Family Kinases Negatively Regulate Platelet-derived Growth
Factor
Receptor-dependent Signaling and Disease
Progression*
§,,,
,, and**
The Schepens Eye Research Institute, Harvard
Medical School, Boston, Massachusetts 02114, the ¶ Program in
Developmental Biology, and Division of Basic Sciences, Fred Hutchinson
Cancer Research Center, Seattle, Washington 98109, and the
Lymphocyte Biology Section, Division of Rheumatology, Immunology
and Allergy, Department of Medicine, Brigham and Women's Hospital,
Harvard Medical School, Boston, Massachusetts 02115
receptor (PDGFR). 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 PDGFR.
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 PDGFR, and that the SFK/c-Cbl suppression of
PDGFR output is relevant to the onset and progression of a
proliferative disease.
*
This work was supported in part by National Institutes of
Health Grant EY11693 (to A. K.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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