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

Stephan Rosenkranz, Yasushi Ikuno, Fee Lai Leong, Richard A. Klinghoffer, Sachiko Miyake, Hamid Band, Andrius Kazlauskas

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9620-9627
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number13
DOIs
StatePublished - Mar 31 2000

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Platelet-Derived Growth Factor Receptors
src-Family Kinases
Disease Progression
Cells
Degradation
Half-Life
Retinal Diseases
Tissue culture
S Phase
Cultured Cells
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Src family kinases negatively regulate platelet-derived growth factor α receptor-dependent signaling and disease progression. / Rosenkranz, Stephan; Ikuno, Yasushi; Leong, Fee Lai; Klinghoffer, Richard A.; Miyake, Sachiko; Band, Hamid; Kazlauskas, Andrius.

In: Journal of Biological Chemistry, Vol. 275, No. 13, 31.03.2000, p. 9620-9627.

Research output: Contribution to journalArticle

Rosenkranz, Stephan ; Ikuno, Yasushi ; Leong, Fee Lai ; Klinghoffer, Richard A. ; Miyake, Sachiko ; Band, Hamid ; Kazlauskas, Andrius. / Src family kinases negatively regulate platelet-derived growth factor α receptor-dependent signaling and disease progression. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 13. pp. 9620-9627.
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