Molecular Cell
Volume 27, Issue 5, 7 September 2007, Pages 717-730
Journal home page for Molecular Cell

Article
A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases

https://doi.org/10.1016/j.molcel.2007.06.028Get rights and content
Under an Elsevier user license
open archive

Summary

Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory “molecular brake” mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.

SIGNALING

Cited by (0)

4

These authors contributed equally to this work.