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

J Biol Chem. 2003 Aug 22;278(34):31461-4. doi: 10.1074/jbc.C300186200. Epub 2003 Jun 24.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Chromatography, Liquid
  • Dimerization
  • Humans
  • Mass Spectrometry
  • Phosphorylation
  • Phosphotransferases / genetics*
  • Protein Conformation
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-kit / chemistry
  • Proto-Oncogene Proteins c-kit / physiology*
  • Transcriptional Activation / physiology*

Substances

  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Phosphotransferases
  • Proto-Oncogene Proteins c-kit