critical role of flrt1 phosphorylation in the interdependent regulation of flrt1 function and fgf receptor signalling关键作用flrt1磷酸化的相互依存的监管flrt1功能和fgf受体信号.pdfVIP

Critical Role of FLRT1 Phosphorylation in the Interdependent Regulation of FLRT1 Function and FGF Receptor Signalling 1 2¤ 3 3 2 4 Lee M. Wheldon , Bryan P. Haines , Rajit Rajappa , Ivor Mason , Peter W. Rigby , John K. Heath * 1 Molecular Bacteriology and Immunology Group (MBIG), Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom, 2 Section of Gene Function and Regulation, The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom, 3 MRC Centre for Developmental Neurobiology, King’s College London, London, United Kingdom, 4 Cancer Research UK Growth Factor Group, School of Biosciences, University of Birmingham, Birmingham, United Kingdom Abstract Background: Fibronectin leucine rich transmembrane (FLRT) proteins have dual properties as regulators of cell adhesion and potentiators of fibroblast growth factor (FGF) mediated signalling. The mechanism by which the latter is achieved is still unknown and is the subject of this investigation. Principal Findings: Here we show that FLRT1 is a target for tyrosine phosphorylation mediated by FGFR1 and implicate a non-receptor Src family kinase (SFK). We identify the target tyrosine residues in the cytoplasmic domain of FLRT1 and show that these are not direct substrates for Src kinase suggesting that the SFK may exert effects via potentiation of FGFR1 kinase activity. We show that whilst FLRT1 expression results in a ligand-dependent elevation of MAP kinase activity, a mutant version of FLRT1, defective as an FGFR1 kinase substrate (Y3F-FLRT1), has the property of eliciting ligand-independent chronic activation of the MAP kinase pathway which is suppressed by pharmacological inhibition of either FGFR1 or Src