Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ

Zhifeng Huang, William M. Marsiglia, Upal Basu Roy, Nader Rahimi, Dariush Ilghari, Huiyan Wang, Huaibin Chen, Weiming Gai, Steven Blais, Thomas A. Neubert, Alka Mansukhani, Nathaniel J. Traaseth, Xiaokun Li, Moosa Mohammadi

Research output: Contribution to journalArticle

Abstract

The molecular basis by which receptor tyrosine kinases (RTKs) recruit and phosphorylate Src Homology 2 (SH2) domain-containing substrates has remained elusive. We used X-ray crystallography, NMR spectroscopy, and cell-based assays to demonstrate that recruitment and phosphorylation of Phospholipase Cγ (PLCγ), a prototypical SH2 containing substrate, by FGF receptors (FGFR) entails formation of an allosteric 2:1 FGFR-PLCγ complex. We show that the engagement of pTyr-binding pocket of the cSH2 domain of PLCγ by the phosphorylated tail of an FGFR kinase induces a conformational change at the region past the cSH2 core domain encompassing Tyr-771 and Tyr-783 to facilitate the binding/phosphorylation of these tyrosines by another FGFR kinase in trans. Our data overturn the current paradigm that recruitment and phosphorylation of substrates are carried out by the same RTK monomer in cis and disclose an obligatory role for receptor dimerization in substrate phosphorylation in addition to its canonical role in kinase activation. Substrate recruitment and phosphorylation is a fundamental process in RTK signaling. This study shows how two FGFR kinase molecules act in concert to recruit and transphosphorylate PLCγ, thus overturning the current paradigm that recruitment and phosphorylation of the substrates are carried out by the same RTK in cis.

Original languageEnglish (US)
Pages (from-to)98-110
Number of pages13
JournalMolecular Cell
Volume61
Issue number1
DOIs
StatePublished - Jan 7 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Huang, Z., Marsiglia, W. M., Basu Roy, U., Rahimi, N., Ilghari, D., Wang, H., Chen, H., Gai, W., Blais, S., Neubert, T. A., Mansukhani, A., Traaseth, N. J., Li, X., & Mohammadi, M. (2016). Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ. Molecular Cell, 61(1), 98-110. https://doi.org/10.1016/j.molcel.2015.11.010