Ckit Receptor Tyrosine Kinase

At least 70% of small-cell lung cancers express the kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). C-kit is a type III receptor tyrosine kinase. It is found that interactions between kit and its ligand, SCF, are important in the development and maintenance of hematopoietic cells, melanocytes, germ cells, and the interstitial cells. SCF acts either alone or in combination with other growth factors in promoting the survival and self-renewal of stem cells, and the proliferation, differentiation, and migration of various cell types. Numerous lines of evidence have demonstrated that this coexpression constitutes a functional autocrine loop, suggesting that inhibitors of kit tyrosine activity could have therapeutic efficacy in this disease. The kit receptor is a transmembrane protein of 145kDa possessing an extracellular ligand-binding domain with five immunoglobulin-like motifs, a signal transmembrane region, and a cytoplasmic domain that exhibits protein tyrosine kinase activity.31 SCF binding to the c-kit receptor results in autophosphorylation on tyrosines located in the COOH-terminal tail region, which then results in activation of its kinase activity.32 When phosphorylated, these tyrosine residues become docking sites for several intracellular signaling molecules, leading to various cellular responses in different cell types.

Generally, kit is expressed in hematopoietic cells, melanocytes, other neural crest derivatives, and germ cells, as well as in a variety of solid tumors.33 Abnormalities in melanogenesis, hematopoiesis, and gonadogenesis were observed in the mice during development with the c-kit or SCF mutations.34 Until now, kit oncogenic mutations have been identified in exon 2 (myelofibrosis and chronic myelogenous leukemia), exon 11-juxtamembrane domain (mast cell tumors and GISTs), and also in the exon 17 phospho-transferase domain (mast cell tumors and germ cell tumors).35

A number of indolino compounds have shown inhibition of wild-type c-kit, but these were generally inefficient at inhibiting the kinase activity of c-kit with a mutation in the kinase domain (814 murine, 816 human, 817 rat); only SU6577 was effective at the high concentration of 40^M.36'37

There are two major ways that c-kit mediates rapid cell growth in SCLC: (1) through the c-kit/SCF autocrine loop and (2) through the overexpression with increased sensitivity to endogenous SCF. The activation of RAS-MAPK cascade by c-kit in SCLC has been documented by Krystal et al.38

Aloe and Your Health

Aloe and Your Health

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