Going from the N-terminus toward the C-terminus, all RPTKs contain an extracellular ligand-binding domain, a single transmembrane-spanning domain, and an intracellular domain composed of a hydrophilic juxtamembrane (JM) region, followed by the highly conserved tyrosine kinase domain and a hydrophilic C-terminus. Based on structural similarities, Kit/SCF-R belongs to the subclass III of RPTKs that includes the receptors for platelet-derived growth factor (PDGF) α and β, colony-stimulating factor-1 (CSF-1), and the Flt-3/Flk-2 RPTK. These proteins are ~950 to ~1,100 amino acids in length, with ~550 extracellular amino acids and 400-550 intracellular amino acids. Their overall identity is 25-40%, but the identity in their intracellular domains is between 45 and 55%, and in the kinase domains proper between 63 and 85%. They are characterized by five immunoglobulin-like repeats in the extracellular ligand-binding domain and a long (75–100 amino acids) hydrophilic kinase insert region, which interrupts the tyrosine kinase domain between the ATP-binding region and the conserved catalytic base. The Kit/SCF-R is expressed in hematopoietic, melanogenic, and gametogenic precursors and derivatives, and in interstitial cells of Cajal. The development of these cells depends on Kit/SCF-R and its ligand. However, Kit is expressed in numerous other tissues/cell types including mammary duct epithelial cells, thyrocytes, and cerebellar basket cells. Two alternative RNA transcripts, resulting from alternate usage of 50 splice donor sites, generate two forms of Kit/SCF-R in all tissues examined. The only difference is the presence or absence of four additional amino acids, GNNK, in the extracellular domain close to the membrane. When overexpressed, the shorter isoform of Kit/SCF-R (DGNNK-Kit/SCF-R), which is the most prevalent in most tissues examined, is constitutively tyrosine phosphorylated, causes tumorigenesis in nude mice and greater activation of ERK/MAPK. However, DGNNK-Kit/SCK-R has not been directly associated with any tumors in man or mouse.


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