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The c-Kit proto-oncogene is a receptor protein-tyrosine kinase associated with several highly malignant human cancers. Upon binding its ligand, stem cell factor (SCF), c-Kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. Disease-causing human mutations that activate SCF-independent constitutive expression of c-Kit are found in acute myelogenous leukemia, human mast cell disease, and gastrointestinal stromal tumors. We report on the phosphorylation state and crystal structure of a c-Kit product complex. The c-Kit structure is in a fully active form, with ordered kinase activation and phosphate-binding loops. These results provide key insights into the molecular basis for c-Kit kinase transactivation to assist in the design of new competitive inhibitors targeting activated mutant forms of c-Kit that are resistant to current chemotherapy regimes.

Structure of a c-kit product complex reveals the basis for kinase transactivation., Mol CD, Lim KB, Sridhar V, Zou H, Chien EY, Sang BC, Nowakowski J, Kassel DB, Cronin CN, McRee DE, J Biol Chem. 2003 Aug 22;278(34):31461-4. Epub 2003 Jun 24. PMID:12824176

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Chien, E Y.T. | Cronin, C N. | Kassel, D B. | Lim, K B. | McRee, D E. | Mol, C D. | Nowakowski, J. | Sang, B C. | Sridhar, V. | Zou, H. | Autophosphorylation | Kinase | Structure | Transactivation