Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2

Yongyou Zhang, Yongshun Lin, Courtney Bowles, Fen Wang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Fibroblast growth factors (FGFs) are upstream activators of the mitogen-activated protein kinase pathway and mitogens in a wide variety of cells. However, whether the mitogen-activated protein kinase pathway solely accounts for the induction of cell cycle or antiapoptotic activity of the FGF receptor (FGFR) tyrosine kinase is not clear. Here we report that cell cycle inducer Cks1, which triggers ubiquitination and degradation of p27 Kip1, associates with the unphosphorylated form of FGFR substrate 2 (FRS2), an adaptor protein that is phosphorylated by FGFR kinases and recruits downstream signaling molecules. FGF-dependent activation of FGFR tyrosine kinases induces FRS2 phosphorylation, causes release of Cks1 from FRS2, and promotes degradation of p27Kip1 in 3T3 cells. Since degradation of p27Kip1 is a key regulatory step in activation of the cyclin E/A-Cdk complex during the G1/S transition of the cell cycle, the results suggest a novel mitogenic pathway whereby FGF and other growth factors that activate FRS2 directly activate cyclin-dependent kinases.

Original languageEnglish (US)
Pages (from-to)55348-55354
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number53
DOIs
StatePublished - Dec 31 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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