IntroductionThe proto-oncogene c-kit encodes the transmembrane type III tyrosine kinase, KIT protein, 1 which is the receptor for stem cell factor (SCF). [2][3][4][5] The subfamily of tyrosine kinases to which KIT belongs includes receptors for platelet-derived growth factor, macrophage colony-stimulating factor, and FLT3 ligand. These receptors are characterized structurally by 5 immunoglobulin-like extracellular domains and by an intracytoplasmic domain that contains an adenosine triphosphate (ATP)-binding domain and a phosphotransferase domain separated by an interkinase sequence. 1,6 Under normal circumstances, SCF binds to KIT, inducing homodimerization of the receptor that leads to intrinsic kinase activity and results in autophosphorylation of tyrosine residues. 7 KIT then becomes the docking site for various Src homology domain 2 (SH2) domain signaling molecules. KIT is expressed on melanocytes, mast cells, primitive hematopoietic cells, primordial germ cells, intraepithelial lymphocytes, and interstitial cells of Cajal. 8,9 Activating mutations within c-kit, first identified by Besmer et al 10 as the cellular homologue of viral oncogene v-kit, were later described in various neoplastic diseases including mastocytosis 11 and gastrointestinal stromal tumors (GISTs). 12 Activating mutations cause constitutive phosphorylation of KIT protein that is independent of ligand binding. 13 Important downstream signaling pathways are inappropriately activated, and this is believed to contribute to the abnormal proliferation and survival of these neoplastic cells. Examples of signaling pathways activated by KIT include the Ras-Raf-MAP kinase cascade, the phosphatidylinositol-3-kinase-AKT cascade, the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, and Src family kinases. 14,15 Mastocytosis, defined as a pathologic increase in the number of mast cells in tissue, is a heterogeneous disease varying in clinical significance from skin involvement alone to systemic involvement with infiltration of the gastrointestinal tract, spleen, and bone marrow. 16 The childhood form is usually a self-limited cutaneous form not generally associated with mutated KIT protein, although exceptions have been published, whereas the sporadic adult systemic form of the disease is always associated with KITactivating mutations. 17 Two types of mutations have been well described. 18 The first mutation is a single residue substitution of valine for aspartic acid at codon 816 (Asp816Val) and lies in the kinase domain of KIT. 11 Mutations at this codon are present in the majority of cases of adult systemic mastocytosis. 17 The second type of mutation includes single residue substitutions and in-frame insertions or deletions in the intracellular juxtamembrane region of KIT protein. 19 It has recently been proposed that this region is an autonomously folded autoinhibitory domain that when compromised by mutation leads to increased activity of KIT. 20 Juxtamembrane mutations are found consistently in diseases such as...
