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

Abstract

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.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930014
Report Number(s):
BNL-80628-2008-JA
TRN: US200822%%1165
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cell; Journal Volume: 27; Journal Issue: 5
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; MUTANTS; MUTATIONS; NEOPLASMS; PHOSPHOTRANSFERASES; RECEPTORS; REGULATIONS; RESIDUES; SKELETON; TYROSINE; national synchrotron light source

Citation Formats

Chen,H., Ma, J., Li, W., Eliseenkova, A., Xu, C., Neubert, T., Miller, W., and Mohammadi, M. A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases. United States: N. p., 2007. Web. doi:10.1016/j.molcel.2007.06.028.
Chen,H., Ma, J., Li, W., Eliseenkova, A., Xu, C., Neubert, T., Miller, W., & Mohammadi, M. A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases. United States. doi:10.1016/j.molcel.2007.06.028.
Chen,H., Ma, J., Li, W., Eliseenkova, A., Xu, C., Neubert, T., Miller, W., and Mohammadi, M. Mon . "A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases". United States. doi:10.1016/j.molcel.2007.06.028.
@article{osti_930014,
title = {A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases},
author = {Chen,H. and Ma, J. and Li, W. and Eliseenkova, A. and Xu, C. and Neubert, T. and Miller, W. and Mohammadi, M.},
abstractNote = {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.},
doi = {10.1016/j.molcel.2007.06.028},
journal = {Molecular Cell},
number = 5,
volume = 27,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
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