Fibroblast growth factors mediate cellular responses by interacting with a family of related receptor tyrosine kinases (FGFRs). We have previously shown that FGFR-1, but not of FGFR-4, ectopically expressed in BaF3 lymphoid cells allows for proliferation in response to FGFs, and that the intracellular signaling halves of these two receptors distinguish their mitogenic potentials (Wang et al., 1994). In order to map the residues which functionally distinguish these receptors, a panel of chimeric receptors whose cytodomains bear dierent contributions from FGFR-1 and FGFR-4 were constructed and characterized. The behavior of these chimeras implicate amino acids from both the kinase insert and kinase domains in receptor-mediated proliferation. Speci®cally, two tyrosine residues present in the short kinase insert domain of FGFR-1 and absent from FGFR-4 are a necessary, but not sucient, component of a fully mitogenic receptor, suggesting that tyrosine phosphorylation in the kinase insert promotes a mitogenic signaling pathway. A strongly mitogenic receptor also requires one or two FGFR-1-speci®c residues from either of two regions within the kinase domain. One of these regions is within the kinase domain's activation loop, where FGFR-1, but not FGFR-4, bears a key aspartate residue. The mitogenic potentials of FGFR-1, FGFR-4, and the chimeric receptors strongly correlates with the magnitude of ligand-induced receptor autophosphorylation in BaF3 cells. We discuss mechanisms by which these few key amino acid dierences may determine the levels of ligand-induced FGF receptor autophosphorylation and mitogenic potency.
Fibroblast growth factor (FGF) receptors (FGFRs) are structurally related receptor protein tyrosine kinases encoded by four distinct genes. Activation of FGFR-1, -2, and -3 by FGFs induces mitogenic responses in various cell types, but the mitogenic potential of FGFR-4 has not been previously explored. We have compared the properties of BaF3 murine lymphoid cells and L6 rat myoblast cells engineered to express FGFR-1 or FGFR-4. Acidic FGF binds with high affinity to and elicits tyrosine phosphorylation of FGFR-1 or FGFR-4 receptors displayed on BaF3 cells, but only FGFR-1 activation leads to cell survival and growth. FGFR-4 activation also fails to elicit detectable signals characteristic of the FGFR-1 response: tyrosine phosphorylation of SHC and extracellular signal-related kinase (ERK) proteins and induction of fos and tis11 RNA expression. The only detected response to FGFR-4 activation was weak phosphorylation of phospholipase C gamma. A chimeric receptor containing the extracellular domain of FGFR-4 and the intracellular domain of FGFR-1 confers FGF-dependent growth upon transfected BaF3 cells, demonstrating that the intracellular domains of the receptors dictate their functional capacity. Activation of FGFR-1 in transfected L6 myoblasts induced far stronger phosphorylation of phospholipase C gamma, SHC, and ERK proteins than could activation of FGFR-4 in L6 cells, and only FGFR-1 activation induced tyrosine phosphorylation of a characteristic 80-kD protein. Hence, the signaling and biological responses elicited by different FGF receptors substantially differ.
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