Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Structure of a c-kit product complex reveals the basis for kinase transactivation. 1282 76

The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.
 ...
PMID:Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. 1512 10

The c-Kit receptor protein-tyrosine kinase plays a critical role in the differentiation, growth and survival of mast cells. Binding of its ligand stem cell factor (SCF), induces c-Kit dimerization, autophosphorylation, and recruitment of signaling proteins. The juxtamembrane sequence of c-Kit contains recruitment sites for the Src family kinases Fyn and Lyn, as well as Shp1 and Shp2 protein-tyrosine phosphatases. To characterize the role of Fyn in c-Kit signaling, we generated bone marrow-derived mast cells (BMMCs) from wild-type and Fyn knock-out mice. In contrast with previous studies of Lyn-deficient BMMCs, SCF treatment of Fyn-deficient BMMCs revealed no overt defects in the overall pattern of tyrosine phosphorylation, phosphatidylinositol 3' kinase recruitment to c-Kit, or phosphorylation of Stat3 transcription factor. However, Fyn-deficient mast cells showed a significant reduction in phosphorylation of Shp2 phosphatase and p38 mitogen-activated protein kinase. Defects in Shp2 and p38 phosphorylation were restored in Fyn-deficient mast cells transduced with a Fyn-expressing retrovirus (Fyn-rescue). Fyn-deficient BMMCs displayed reduced chemotaxis towards SCF, and this defect was corrected in Fyn-rescue cells. This study provides evidence that recruitment of both Shp2 and Fyn to juxtamembrane sites in c-Kit results in Shp2 phosphorylation, downstream signaling to p38 mitogen-activated protein kinase, and enhanced chemotaxis of mast cells.
 ...
PMID:Fyn kinase acts upstream of Shp2 and p38 mitogen-activated protein kinase to promote chemotaxis of mast cells towards stem cell factor. 1644 78