KIT and Melanoma: Biological Insights and Clinical Implications

ITS RTKs FAMILYc-KIT or CD117 is a member of class III transmembrane receptor tyrosine kinases (RTKs) along with platelet-derived growth factor receptors (PDGFRs), fms like tyrosine kinase 3 (FLT3)/ CD135, and macrophage colony stimulating factor receptors (M-CSFRs).It was discovered in 1987 as a cellular homologue of viral oncogene v-kit, which was isolated from a feline retro-virus. 1,2A variety of cell types were identified to express c-KIT including hematopoietic cells, germ cells, gastrointestinal (GI) tract Cajal cells, melanoma cells, B cell progenitors, and mast cells.Wild-type c-KIT protein contains 976 amino acids (aa) divided into three main regions including an extracellular ligand-binding domain with 519 aa, a hydrophobic transmembrane domain with 23 aa, and an intracellular tail (Fig. 1). 3,4he extracellular domain consists of five immunoglobulin-like domains D1-D5, in which D1-D3 is responsible for stem cell factor (SCF) binding while D4-D5 contains motif for receptor dimerization.The 433 aa cytoplasmic region includes a juxtamembrane domain and a tyrosine kinase domain with an insertion of approximately 80 residues.Most of phosphorylation sites on c-KIT are located at the juxta-membrane region, the kinase insertion domain, and the C-terminal tail.Human c-KIT is encoded by a proto-oncogene located on the chromosome 4 at position of q11-12. 5This 90 kb gene is transcribed and translated into a core protein of 110 kDa, which is subsequently heterogeneously N-linked glycosylated, mainly in the extra-