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Structure of a c-kit product complex reveals the basis for kinase transactivation.

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Mol C.D., Lim K.B., Sridhar V., Zou H., Chien E.Y., Sang B.C., Nowakowski J., Kassel D.B., Cronin C.N., McRee D.E.

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.

J. Biol. Chem. 278:31461-31464(2003) [PubMed] [Europe PMC]