Proto-oncogene c-KIT is the gene encoding thereceptor tyrosine kinase protein known astyrosine-protein kinase KIT,CD117 (cluster of differentiation 117) ormast/stem cell growth factor receptor (SCFR).[5] Multiple transcript variants encoding different isoforms have been found for this gene.[6][7]KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.[8]
KIT is acytokine receptor expressed on the surface ofhematopoietic stem cells as well as other cell types. Altered forms of this receptor may be associated with some types ofcancer.[9] KIT is areceptor tyrosine kinase type III, which binds tostem cell factor, also known as "steel factor" or "c-kit ligand". When this receptor binds tostem cell factor (SCF) it forms adimer that activates its intrinsic tyrosine kinase activity, that in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell.[10] After activation, the receptor is ubiquitinated to mark it for transport to alysosome and eventual destruction. Signaling through KIT plays a role in cell survival, proliferation, and differentiation. For instance, KIT signaling is required formelanocyte survival, and it is also involved inhaematopoiesis andgametogenesis.[11]
Like other members of thereceptor tyrosine kinase III family, KIT consists of an extracellular domain, a transmembrane domain, a juxtamembrane domain, and an intracellular tyrosine kinase domain. The extracellular domain is composed of five immunoglobulin-like domains, and the protein kinase domain is interrupted by a hydrophilic insert sequence of about 80 amino acids. The ligandstem cell factor binds via the second and third immunoglobulin domains.[12][10][13]
CD117/c-KIT is expressed not only by bone marrow-derived stem cells, but also by those found in other adult organs, such as the prostate, liver, and heart, suggesting that SCF/c-KIT signaling pathways may contribute to stemness in some organs. Additionally, c-KIT has been associated with numerous biological processes in other cell types. For example, c-KIT signaling, has been shown to regulate oogenesis, folliculogenesis, and spermatogenesis, playing important roles in female and male fertility.[16]
Hematopoietic progenitor cells are normally present in the blood at low levels. Mobilization is the process by which progenitors are made to migrate from the bone marrow into the bloodstream, thus increasing their numbers in the blood. Mobilization is used clinically as a source of hematopoietic stem cells forhematopoietic stem cell transplantation (HSCT). Signaling through KIT has been implicated in mobilization. At the current time,G-CSF is the main drug used for mobilization; it indirectly activates KIT.Plerixafor (an antagonist ofCXCR4-SDF1) in combination with G-CSF, is also being used for mobilization of hematopoietic progenitor cells. Direct KITagonists are currently being developed as mobilization agents.
c-KIT plays an important role in regulating many mechanisms leading to tumor formation and progression of carcinomas. c-KIT has been proposed as a regulator of stemness in several cancers. Its expression has been linked to cancer stemness in ovarian cancer cells, colon cancer cells, non-small cell lung cancer cells, and prostate cancer cells. c-KIT has also been linked to the epithelial-mesenchymal transition (EMT), which is important for tumor aggressiveness and metastatic potential. Ectopic expression of c-KIT and EMT have been linked in denoid cystic carcinoma of the salivary gland, thymic carcinomas, ovarian cancer cells, and prostate cancer cells. Several lines of evidence suggest that SCF/c-KIT signaling plays an important role in the tumor microenvironment. For example, in mice high levels of c-KIT in mast cells as well as its presence in the tumor microenvironment promote angiogenesis, leading to increased tumor growth and metastasis.[16]
KIT is aproto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.[17] Seminomas, a subtype of testiculargerm cell tumors, frequently have activating mutations in exon 17 of KIT. In addition, the gene encoding KIT is frequently overexpressed and amplified in this tumor type, most commonly occurring as asingle gene amplicon.[18] Mutations of KIT have also been implicated inleukemia, a cancer of hematopoietic progenitors,melanoma, mast cell disease, andgastrointestinal stromal tumors (GISTs). The efficacy ofimatinib (trade name Gleevec), a KIT inhibitor, is determined by the mutation status of KIT:
When the mutation has occurred in exon 11 (as is the case many times in GISTs), the tumors are responsive toimatinib. However, if the mutation occurs in exon 17 (as is often the case in seminomas and leukemias), the receptor is not inhibited byimatinib. In those cases other inhibitors such asdasatinib Avapritinib ornilotinib can be used. Researchers investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting computational analysis.[19] Their atomic investigation of mutant KIT receptor which emphasized on the EAL region provided a better insight into the understanding of the sunitinib resistance mechanism of the KIT receptor and could help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.[19]
Antibodies to KIT are widely used inimmunohistochemistry to help distinguish particular types of tumour inhistological tissue sections. It is used primarily in the diagnosis of GISTs, which are positive for KIT, but negative for markers such asdesmin andS-100, which are positive insmooth muscle and neural tumors, which have a similar appearance. In GISTs, KIT staining is typicallycytoplasmic, with stronger accentuation along thecell membranes. KIT antibodies can also be used in the diagnosis ofmast cell tumours and in distinguishingseminomas fromembryonal carcinomas.[21]
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