Structure of a c-kit product complex reveals the basis for kinase transactivation.
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.
Mol
Clifford D
CD
Syrrx, Inc., San Diego, California 92121, USA.
Lim
Kheng B
KB
Sridhar
Vandana
V
Zou
Hua
H
Chien
Ellen Y T
EY
Sang
Bi-Ching
BC
Nowakowski
Jacek
J
Kassel
Daniel B
DB
Cronin
Ciarán N
CN
McRee
Duncan E
DE
D002853:Chromatography, Liquid; D019281:Dimerization; D006801:Humans; D013058:Mass Spectrometry; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics*; D011487:Protein Conformation; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D010770:Phosphotransferases; D019009:Proto-Oncogene Proteins c-kit