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Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis

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Abstract

STIMULATION of certain receptor tyrosine kinases results in the tyrosine phosphorylation and activation of phospholipase Cγ(PLCγ), an enzyme that catalyses the hydrolysis of phosphatidylinositol (Ptdlns)1–8. This hydrolysis generates diacylglycerol and free inositol phosphate, which in turn activate protein kinase C and increase intracellular Ca2+, respectively. PLCγ physically associates with activated receptor tyrosine kinases, suggesting that it is a substrate for direct phosphorylation by these kinases7–10. Here we report that a fibroblast growth factor (FGF) receptor with a single point mutation at residue 766 replacing tyrosine with phenylalanine fails to associate with PLCγ in response to FGF. This mutant receptor also failed to mediate Ptdlns hydrolysis and Ca2+ mobilization after FGF stimulation. However, the mutant receptor phosphorylated itself and several other cellular proteins, and it mediated mitogenesis in response to FGF. These findings show that a point mutation in the FGF receptor selectively eliminates activation of PLCγ and that neither Ca2+ mobilization nor Ptdlns hydrolysis are required for FGF-induced mitogenesis.

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Author notes

  1. Jacky Marie

    Present address: Centre CNRS-INSERM de Pharmacologie-Endocrinologie, rue de la Cardonille, 34094, Montpellier, France

Authors and Affiliations

  1. Program of Excellence in Molecular Biology, Cardiovascular Research Institute, University of California, 533 Parnassus Avenue, San Francisco, California, 94143-0724, USA

    Kevin G. Peters, Jacky Marie, Emily Wilson, Harlan E. Ives, Jaime Escobedo, Mercedita Del Rosario, Daniel Mirda & Lewis T. Williams

  2. Division of Nephrology, and Howard Hughes Medical Institute, University of California, 533 Parnassus Avenue, San Francisco, California, 94143-0724, USA

    Emily Wilson & Harlan E. Ives

Authors
  1. Kevin G. Peters
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Peters, K., Marie, J., Wilson, E. et al. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis. Nature 358, 678–681 (1992). https://doi.org/10.1038/358678a0

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  • DOI: https://doi.org/10.1038/358678a0

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