@article{78a5d32993d245cdab298f4226c2965e,
title = "Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ",
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.",
author = "Zhifeng Huang and Marsiglia, {William M.} and {Basu Roy}, Upal and Nader Rahimi and Dariush Ilghari and Huiyan Wang and Huaibin Chen and Weiming Gai and Steven Blais and Neubert, {Thomas A.} and Alka Mansukhani and Traaseth, {Nathaniel J.} and Xiaokun Li and Moosa Mohammadi",
note = "Funding Information: The authors are thankful to Dr. Regina Goetz and Mr. Yang Liu for critically reading the manuscript and for making thoughtful suggestions. This work was supported by the U.S. NIH NIDCR Grant DE13686 (to M.M.), NIH/NEI (R21CA191970 and R21CA193958) (to N.R.), NINDS grant P30 NS050276 (to T.A.N.), grants from Natural Science Foundation of China 81473261, 31270789 (to Z.H. and H.C.) and the St Baldrick{\textquoteright}s Foundation (to A.M.), and start-up funded from NYU (to N.J.T.). The NMR data collected at NYU was supported by an NIH S10 grant (OD016343) while the data collected at NYSBC was made possible by a grant from NYSTAR and ORIP/NIH facility improvement grant CO6RR015495. The 900 MHz NMR spectrometer was purchased with funds from NIH grant P41GM066354, the Keck Foundation, New York State Assembly, and U.S. Dept. of Defense. The coordinates and structure factors for the complex will be deposited in the RCSB Protein Data Bank under released upon acceptance of the manuscript. The coordinates and structure factors for the 1:1 FGFR2K pY769 - PLCγ cSH2 complex reported in this manuscript are publicly available at the World Wide Protein Data Bank (wwPDB) under PDB: 5EG3 . Funding Information: The authors are thankful to Dr. Regina Goetz and Mr. Yang Liu for critically reading the manuscript and for making thoughtful suggestions. This work was supported by the U.S. NIH NIDCR Grant DE13686 (to M.M.), NIH/NEI (R21CA191970 and R21CA193958) (to N.R.), NINDS grant P30 NS050276 (to T.A.N.), grants from Natural Science Foundation of China 81473261, 31270789 (to Z.H. and H.C.) and the St Baldrick{\textquoteright}s Foundation (to A.M.), and start-up funded from NYU (to N.J.T.). The NMR data collected at NYU was supported by an NIH S10 grant (OD016343) while the data collected at NYSBC was made possible by a grant from NYSTAR and ORIP/NIH facility improvement grant CO6RR015495. The 900 MHz NMR spectrometer was purchased with funds from NIH grant P41GM066354, the Keck Foundation, New York State Assembly, and U.S. Dept. of Defense. The coordinates and structure factors for the complex will be deposited in the RCSB Protein Data Bank under released upon acceptance of the manuscript. The coordinates and structure factors for the 1:1 FGFR2KpY769- PLCγcSH2 complex reported in this manuscript are publicly available at the World Wide Protein Data Bank (wwPDB) under PDB: 5EG3. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = jan,
day = "7",
doi = "10.1016/j.molcel.2015.11.010",
language = "English (US)",
volume = "61",
pages = "98--110",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",
}