C-Kit receptor tyrosine kinase

Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. 2000. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96 925-32... 

As mentioned earlier, 70% of SCLC express the kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Several studies determined that inhibitors of kit tyrosine kinase activity could have therapeutic efficacy in this disease. SCF-induced c-kit phosphorylation was found to be inhibited by PP2 (4-chlorophenyl-7-t-butyl-pyrazolo... 

Blanke CD, Rankin C, Demetri GD et al. (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase S0033. J Clin Oncol 26 626-632... 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

Kit/KL mast cell growth factor, stem cell or steel factor Two heterogeneously glycosylated forms. KL-1, KL-2. Role In haemalopoiesis and in the development of cell lineages c-Kit receptor Receptor tyrosine kinase... 

Stem cell factor, SCF, also called steel factor or mast cell growth factor is a cytokine that stimulates the proliferation of myeloid and lymphoid hemopoietic progenitor cells. SCF is a ligand of the receptor tyrosine kinase, c-KIT, a protoonct ene. The KIT oncogene is the gene of a transforming feline sarcoma virus. 

BAY 43-9006 (Sorafenib Bayer/Onyx Pharmaceuticals, Emeryville, CA) is a biaryl urea that inhibits Raf-1 kinase activity in vitro with IC50 value of 6nM, and B-Raf with IC50 value of 22 nM (25). This compound also inhibits some receptor tyrosine kinases, which include VEGF receptor family members, PDGF receptor. Fit, and c-Kit, at close to the same potency. 

Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, et al. 1987. Human proto-oncogene c-kit a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 6 3341-51... 

C-kit is a transmembrane glycoprotein receptor tyrosine kinase with homologies to the platelet-derived growth... 

Imatinib is a protein-tyrosine-kinase inhibitor. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive (Ph-r) chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells and BCR-ABL positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. It is indicated in the treatment of newly diagnosed adult patients with Ph-t CML in chronic phase patients with Ph-t CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment children with Ph-t chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy and treatment of gastrointestinal stromal tumors (GIST). 

S ATP -h phosphatidylinositol 3-kinase <57> (<57>, binding of c-kit ligand, stem cell factor SCF to c-kit receptor c-kitR is known to activate c-kitR tyrosine kinase, thereby leading to autophosphorylation of c-kitR on Tyr and to association of c-kitR with substrates such as phosphatidylinositol 3-kinase [172]) (Reversibility <57> [172]) [172]... 

Matthews, W. Jordan, C.T. Gavin, M. Jenkins, N.A. Copeland, N.G. Le-mischka, I.R. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc. Natl. Acad. Sci. USA, 88, 9026-9030 (1991)... 

RTKs represent pivotal targets in approaches toward cancer therapy. Thns, c-Met, c-Kit, as well as EGFR are important receptor tyrosine kinases that have been implicated in the etiology of multiple tumor types, and they are important therapeutic targets. 

Some neuroblastoma cells overexpress the c-Kit receptor for its ligand, stem cell factor (SCF), and release SCF in an autocrine loop for self-stimulation of mitoses. Imatinib mesylate suppresses PDGF and tyrosine kinase c-Kit (GDI 17) expression. Somatostatin inhibited PDGF-induced phosphorylation of PDGFR and inhibited ras gene amplification. For local invasion, these tumor cells release MMP2/9. The synthetic MMP inhibitor, prinomastat, suppresses MMP production and tumor cell locomotion. However, MMP expression is promotional for neuroblastoma cell differentiation. The presence of MMP is necessary for the neurite formation of retinoic acid-treated neuroblastoma cells neurite formation is the first sign of differentiation induction (vide infra) [1624]. 

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