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

Zhifeng Huang1, William M Marsiglia2, Upal Basu Roy3

  • 1School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.

Molecular Cell
|December 22, 2015
PubMed

Insights

Receptor tyrosine kinases (RTKs) recruit and phosphorylate substrates like Phospholipase Cγ (PLCγ) through a novel allosteric complex. This process requires receptor dimerization, overturning the previous understanding of substrate phosphorylation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Signaling

Background:

  • Receptor tyrosine kinases (RTKs) are crucial cell surface receptors involved in various cellular processes.
  • The mechanism by which RTKs recruit and phosphorylate Src Homology 2 (SH2) domain-containing substrates is not fully understood.
  • Phospholipase Cγ (PLCγ) is a key substrate containing an SH2 domain, implicated in signal transduction.

Purpose of the Study:

  • To elucidate the molecular mechanism of substrate recruitment and phosphorylation by RTKs.
  • To investigate the role of receptor dimerization in the phosphorylation of SH2 domain-containing substrates.

Main Methods:

  • X-ray crystallography
  • NMR spectroscopy
  • Cell-based assays

Main Results:

  • Demonstrated an allosteric 2:1 complex formation between FGF receptors (FGFR) and PLCγ.
  • Showed that FGFR-PLCγ complex formation induces conformational changes facilitating trans-phosphorylation.
  • Overturned the paradigm of cis-phosphorylation by a single RTK monomer.

Conclusions:

  • Receptor dimerization is obligatory for substrate phosphorylation, beyond its role in kinase activation.
  • The study reveals a new mechanism for RTK-mediated substrate phosphorylation involving allosteric complex formation.

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