Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation

To decipher the mechanism involved in Grb14 binding to the activated fibroblast growth factor receptor (FGFR), we used the bioluminescence resonance energy transfer (BRET) technique and the Xenopus oocyte model. We showed that Grb14 was recruited to FGFR1 into a trimeric complex containing also phospholipase C gamma (PLC gamma). The presence of Grb14 altered FGF-induced PLC gamma phosphorylation and activation. Grb14-FGFR interaction involved the Grb14-SH2 domain and the FGFR pY766 residue, which is the PLC gamma binding site. Our data led to a molecular model whereby Grb14 binding to the phosphorylated FGFR induces a conformational change that unmasks a PLC gamma binding motif on Grb14, allowing trapping and inactivation of PLC gamma. Structured summary: MINT-8019680: Grb14 (uniprotkb:O88900) physically interacts (MI:0915) with FGFR1 (uniprotkb:P11362) by anti tag coimmunoprecipitation (MI: 0007) MINT-8019693, MINT-8019727: Grb14 (uniprotkb:O88900) physically interacts (MI: 0915) with FGFR1 (uniprotkb: P11362) by bioluminescence resonance energy transfer (MI:0012) MINT-8019714, MINT-8019746: PLC gamma1 (uniprotkb:P19174) physically interacts (MI: 0915) with FGFR1 (uniprotkb: P11362) by bioluminescence resonance energy transfer (MI: 0012) (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.