Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2.
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 p27(Kip1) in 3T3 cells. Since degradation of p27(Kip1) is a key regulatory step in activation of the cyclin E/A-Cdk complex during the G(1)/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.
Zhang
Yongyou
Y
Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A & M University System Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030-3303, USA.
Lin
Yongshun
Y
Bowles
Courtney
C
Wang
Fen
F
D016475:3T3 Cells; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018076:DNA, Complementary / Q000378:metabolism; D016193:G1 Phase; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D016196:S Phase; D012685:Sepharose / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; C488187:FRS2alpha protein, mouse; D006133:Growth Substances; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014443:Tyrosine; D012685:Sepharose; D005982:Glutathione Transferase; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D042846:CDC2-CDC28 Kinases; C474110:Cks1 protein, mouse; D005978:Glutathione