TI  - Signal transduction pathway of human <prot>fibroblast growth factor receptor 3</prot>.
      Identification of a novel 66-kDa phosphoprotein.
PG  - 6621-8
AB  - Stimulation of <prot>fibroblast growth factor receptor 3</prot> (<prot>FGFR3</prot>) results in a
      variety of functional effects, including regulation of epithelial cell
      growth and differentiation. In order to characterize the signaling pathway
      through which <prot>FGFR3</prot> regulates cell growth, L6 cells lacking any endogenous
      FGFR were stably transfected with the two different human isoforms, <prot><prot>FGFR3</prot>
      IIIb</prot> and <prot><prot>FGFR3</prot> IIIc</prot>, that result from alternative splicing of exon III of
      the <prot>FGFR3</prot> gene encoding the ligand binding domain. Expression of <prot><prot>FGFR3</prot>
      IIIc</prot> in stably transfected L6 cells conferred growth responses to several
      members of the FGF family including <prot>FGF-1</prot>, -2, -4, and -6, while <prot><prot>FGFR3</prot>
      IIIb</prot>-expressing cells responded only to <prot>FGF-1</prot>. Activation of <prot>FGFR3</prot> upon
      ligand binding resulted in activation of <prot>mitogen-activated protein kinase</prot>
      pathway. <prot>FGFR3</prot> utilizes two different pools of adapter protein <prot>GRB2</prot> to
      link to <prot>Ras</prot>. Activated  <prot>FGFR3</prot>  predominantly interacts with     <prot>GRB2</prot>  . <prot>Sos</prot>    in
      complex with a previously identified 90-kDa protein and designated protein
       <prot>80K-H</prot> . In addition,  <prot>80K-H</prot> . <prot>GRB2</prot> .  <prot>Sos</prot>  complex was found to contain a novel
      66-kDa protein. Tyrosine phophorylation of the 66-kDa protein was
      dependent on ligand activation of <prot>FGFR3</prot>, suggesting that the 66-kDa
      protein may play an important role in <prot>FGFR3</prot>-specific signaling. In
      addition to this unique pathway,  <prot>FGFR3</prot>  also links to   <prot>GRB2</prot> . <prot>Sos</prot>   complex via
      the adapter protein  <prot>Shc</prot> . Furthermore, activated <prot>FGFR3</prot> was not able to
      induce dissociation of  <prot>GRB2</prot> . <prot>Sos</prot>  complex following <prot>Sos</prot> phosphorylation. In
      summary, <prot>FGFR3</prot> signaling pathway utilizes two <prot>GRB2</prot>-containing complexes;
       <prot>Shc</prot> . <prot>GRB2</prot> . <prot>Sos</prot>  and  <prot>80K-H</prot> . <prot>pp66</prot> . <prot>GRB2</prot> . <prot>Sos</prot> ; these two complexes may
      alternatively link <prot>FGFG3</prot> to <prot>mitogen-activated protein kinase</prot>. Finally,
      activated <prot>FGFR3</prot> was also found to result in phosphorylation of
      <prot>phospholipase C-gamma</prot> but reduced phosphorylation of <prot>c-Src</prot>.
AD  - Department of Medicine, Massachusetts General Hospital and Harvard Medical
