Amino acid residues which distinguish the mitogenic potentials of two FGF receptors.
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 different 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. Specifically, two tyrosine residues present in the short kinase insert domain of FGFR-1 and absent from FGFR-4 are a necessary, but not sufficient, 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-specific 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 differences may determine the levels of ligand-induced FGF receptor autophosphorylation and mitogenic potency.
Wang
J K
JK
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Goldfarb
M
M
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000502:physiology; D001483:Base Sequence; D004789:Enzyme Activation; D006133:Growth Substances / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008715:Methionine / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D000596:Amino Acids; D006133:Growth Substances; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D001224:Aspartic Acid; D008715:Methionine; C496349:Fgfr1 protein, mouse; C496372:Fgfr4 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4