SIGNAL-TRANSDUCTION PATHWAY OF HUMAN FIBROBLAST GROWTH-FACTOR RECEPTOR-3 - IDENTIFICATION OF A NOVEL 66-KDA PHOSPHOPROTEIN

Stimulation of fibroblast growth factor receptor 3 (FGFR3) results in a variety of functional effects, including regulation of epithelial ce ll growth and differentiation, In order to characterize the signaling pathway through which FGFR3 regulates cell growth, L6 cells lacking an y endogenous FGFR were stably transfected with the two different human isoforms, FGFR3 IIIb and FGFR3 IIIc, that result from alternative spl icing of exon III of the FGFR3 gene encoding the ligand binding domain , Expression of FGFR3 IIIc in stably transfected L6 cells conferred gr owth responses to several members of the FGF family including FGF-1, - 2, -4, and -6, while FGFR3 IIIb expressing cells responded only to FGF -1, Activation of FGFR3 upon ligand binding resulted in activation of mitogen-activated protein kinase pathway, FGFR3 utilizes two different pools of adapter protein GRB2 to link to Pas, Activated FGFR3 predomi nantly interacts with GRB2 . Sos in complex with a previously identifi ed 90-kDa protein and designated protein 80K-H, In addition, 80K-H . G RB2 . Sos complex was found to con tain a novel 66-kDa protein, Tyrosi ne phophorylation of the 66-kDa protein was dependent on ligand activa tion of FGFR3, suggesting that the 66-kDa protein may play an importan t role in FGFR3-specific signaling, In addition to this unique pathway , FGFR3 also links to GRB2 . Sos complex via the adapter protein Shc. Furthermore, activated FGFR3 was not able to induce dissociation of GR B2 . Sos complex following Sos phosphorylation, In summary, FGFR3 sign aling pathway utilizes two GRB2-containing complexes; Shc . GRB2 . Sos and 80K-H . pp66 . GRB2 . Sos; these two complexes may alternatively link FGFG3 to mitogen-activated protein kinase, Finally, activated FGF R3 was also found to result in phosphorylation of phospholipase C-gamm a but reduced phosphorylation of c-Src.