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

Journal Article · Mon Jan 01 00:00:00 EST 2007 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2007.06.028· OSTI ID:930014

Chen, H; Ma, J; Li, W; Eliseenkova, A; Xu, C; Neubert, T; Miller, W; Mohammadi, M

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.

• Research Organization: Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: DE-AC02-98CH10886
• OSTI ID: 930014
• Report Number(s): BNL-80628-2008-JA; TRN: US200822%%1165
• Journal Information: Molecular Cell, Vol. 27, Issue 5
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
MUTANTS
MUTATIONS
NEOPLASMS
PHOSPHOTRANSFERASES
RECEPTORS
REGULATIONS
RESIDUES
SKELETON
TYROSINE
national synchrotron light source