Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 or mast/stem cell growth factor receptor. Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.
Function
KIT is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. Altered forms of this receptor may be associated with some types of cancer. KIT is a receptor tyrosine kinase type III, which binds to stem cell factor, also known as "steel factor" or "c-kit ligand". When this receptor binds to stem cell factor it forms a dimer that activates its intrinsic tyrosine kinase activity, that in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. After activation, the receptor is ubiquitinated to mark it for transport to a lysosome and eventual destruction. Signaling through KIT plays a role in cell survival, proliferation, and differentiation. For instance, KIT signaling is required for melanocyte survival, and it is also involved in haematopoiesis and gametogenesis.
Structure
Like other members of the receptor 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 ligand stem cell factor binds via the second and third immunoglobulin domains.
Cell surface marker
molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. KIT is an important cell surface marker used to identify certain types of hematopoietic progenitors in the bone marrow. To be specific, hematopoietic stem cells, multipotent progenitors, and common myeloid progenitors express high levels of KIT. Common lymphoid progenitors express low surface levels of KIT. KIT also identifies the earliest thymocyte progenitors in the thymus—early T lineage progenitors and DN2 thymocytes express high levels of c-Kit. It is also a marker for mouse prostate stem cells. In addition, mast cells, melanocytes in the skin, and interstitial cells of Cajal in the digestive tract express KIT. In humans, expression of c-kit in helper-like innate lymphoid cells which lack the expression of CRTH2 is used to mark the ILC3 population.
Mobilization
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 for hematopoietic stem cell transplantation. 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 in combination with G-CSF, is also being used for mobilization of hematopoietic progenitor cells. Direct KIT agonists are currently being developed as mobilization agents.
KIT is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer. Seminomas, a subtype of testicular germ 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 a single gene amplicon. Mutations of KIT have also been implicated in leukemia, a cancer of hematopoietic progenitors, melanoma, mast cell disease, and gastrointestinal stromal tumors. The efficacy of imatinib, a KIT inhibitor, is determined by the mutation status of KIT: When the mutation has occurred in exon 11, the tumors are responsive to imatinib. However, if the mutation occurs in exon 17, the receptor is not inhibited by imatinib. In those cases other inhibitors such as dasatinib and nilotinib can be used. Researchers investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop region by conducting computational analysis. 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. The preclinical agent, KTN0182A, is an anti-KIT, pyrrolobenzodiazepine -containing antibody-drug conjugate which shows anti-tumor activity in vitro and in vivo against a range of tumor types.
Diagnostic relevance
Antibodies to KIT are widely used in immunohistochemistry to help distinguish particular types of tumour in histological tissue sections. It is used primarily in the diagnosis of GISTs, which are positive for KIT, but negative for markers such as desmin and S-100, which are positive in smooth muscle and neural tumors, which have a similar appearance. In GISTs, KIT staining is typically cytoplasmic, with stronger accentuation along the cell membranes. KIT antibodies can also be used in the diagnosis of mast cell tumours and in distinguishing seminomas from embryonal carcinomas.
