KIT (gene)

Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/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
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4U0I, 1PKG, 1T45, 1T46, 2E9W, 2EC8, 2VIF, 3G0E, 3G0F, 4HVS, 4K94, 4K9E, 4PGZ, 2IUH
Identifiers
Aliases	KIT, C-Kit, CD117, PBT, SCFR, KIT proto-oncogene receptor tyrosine kinase, MASTC, KIT proto-oncogene, receptor tyrosine kinase
External IDs	OMIM: 164920 MGI: 96677 HomoloGene: 187 GeneCards: KIT
Gene location (Human) Chr. Chromosome 4 (human)^[1] Band 4q12 Start 54,657,918 bp^[1] End 54,740,715 bp^[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)^[2] Band 5 C3.3|5 39.55 cM Start 75,735,576 bp^[2] End 75,817,382 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte lactiferous duct cardia parotid gland visceral pleura nipple pylorus gastric mucosa ventral tegmental area Region I of hippocampus proper Top expressed in cerebellar vermis secondary oocyte dermis liver parenchyma left lung lobe corneal stroma subiculum right lung right lung lobe parotid gland More reference expression data BioGPS n/a
Gene ontology Molecular function stem cell factor receptor activity kinase activity transmembrane receptor protein tyrosine kinase activity ATP binding cytokine binding protein kinase activity metal ion binding transferase activity protein homodimerization activity protease binding protein binding protein tyrosine kinase activity nucleotide binding phosphatidylinositol-4,5-bisphosphate 3-kinase activity receptor tyrosine kinase transmembrane signaling receptor activity SH2 domain binding Cellular component cytoplasm membrane cell-cell junction cytoplasmic side of plasma membrane cell surface integral component of membrane acrosomal vesicle external side of plasma membrane mast cell granule extracellular space plasma membrane integral component of plasma membrane receptor complex Biological process melanocyte migration myeloid progenitor cell differentiation positive regulation of MAP kinase activity glycosphingolipid metabolic process positive regulation of phospholipase C activity hematopoietic stem cell migration stem cell population maintenance protein phosphorylation T cell differentiation spermatogenesis cell chemotaxis developmental pigmentation melanocyte differentiation positive regulation of Notch signaling pathway lamellipodium assembly cytokine-mediated signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway melanocyte adhesion lymphoid progenitor cell differentiation spermatid development erythrocyte differentiation negative regulation of programmed cell death protein autophosphorylation mast cell degranulation inflammatory response positive regulation of MAPK cascade myeloid leukocyte differentiation male gonad development phosphorylation positive regulation of DNA-binding transcription factor activity epithelial cell proliferation stem cell differentiation detection of mechanical stimulus involved in sensory perception of sound regulation of cell shape ovarian follicle development ectopic germ cell programmed cell death pigmentation Fc receptor signaling pathway response to radiation mast cell cytokine production positive regulation of receptor signaling pathway via JAK-STAT dendritic cell cytokine production visual learning actin cytoskeleton reorganization megakaryocyte development intracellular signal transduction somatic stem cell population maintenance erythropoietin-mediated signaling pathway Kit signaling pathway positive regulation of cell migration somatic stem cell division mast cell chemotaxis MAPK cascade positive regulation of phosphatidylinositol 3-kinase activity positive regulation of pseudopodium assembly positive regulation of gene expression positive regulation of long-term neuronal synaptic plasticity regulation of cell population proliferation cellular response to thyroid hormone stimulus positive regulation of cell population proliferation embryonic hemopoiesis regulation of developmental pigmentation positive regulation of phosphatidylinositol 3-kinase signaling peptidyl-tyrosine phosphorylation mast cell differentiation digestive tract development immature B cell differentiation germ cell migration signal transduction mast cell proliferation positive regulation of vascular associated smooth muscle cell differentiation phosphatidylinositol phosphate biosynthetic process regulation of transcription by RNA polymerase II positive regulation of tyrosine phosphorylation of STAT protein tongue development response to cadmium ion positive regulation of pyloric antrum smooth muscle contraction regulation of bile acid metabolic process positive regulation of small intestine smooth muscle contraction positive regulation of colon smooth muscle contraction positive regulation of protein kinase B signaling hemopoiesis negative regulation of signal transduction cell differentiation negative regulation of apoptotic process positive regulation of ERK1 and ERK2 cascade hematopoietic progenitor cell differentiation B cell differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3815 16590 Ensembl ENSG00000157404 ENSMUSG00000005672 UniProt P10721 P05532 RefSeq (mRNA) NM_000222 NM_001093772 NM_001122733 NM_021099 RefSeq (protein) NP_000213 NP_001087241 NP_001116205 NP_066922 Location (UCSC) Chr 4: 54.66 – 54.74 Mb Chr 5: 75.74 – 75.82 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[9] 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 (SCF) 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.^[10] 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.^[11]

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.^[12][10][13]

Cell surface marker

Cluster of differentiation (CD) 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 (blood) progenitors in the bone marrow. To be specific, hematopoietic stem cells (HSC), multipotent progenitors (MPP), and common myeloid progenitors (CMP) express high levels of KIT. Common lymphoid progenitors (CLP) express low surface levels of KIT. KIT also identifies the earliest thymocyte progenitors in the thymus—early T lineage progenitors (ETP/DN1) and DN2 thymocytes express high levels of c-Kit. It is also a marker for mouse prostate stem cells.^[14] 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 (ILCs) which lack the expression of CRTH2 (CD294) is used to mark the ILC3 population.^[15]

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]

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 (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 of CXCR4-SDF1) 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.

Role in cancer

Activating mutations in this gene are associated with gastrointestinal stromal tumors, testicular seminoma, mast cell disease, melanoma, acute myeloid leukemia, while inactivating mutations are associated with the genetic defect piebaldism.^[6]

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]

Anti-KIT therapies

KIT is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.^[17] 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.^[18] Mutations of KIT have also been implicated in leukemia, a cancer of hematopoietic progenitors, melanoma, mast cell disease, and gastrointestinal stromal tumors (GISTs). The efficacy of imatinib (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 to imatinib. However, if the mutation occurs in exon 17 (as is often the case in seminomas and leukemias), 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 (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]

The preclinical agent, KTN0182A, is an anti-KIT, pyrrolobenzodiazepine (PBD)-containing antibody-drug conjugate which shows anti-tumor activity in vitro and in vivo against a range of tumor types.^[20]

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.^[21]

Interactions

KIT has been shown to interact with:

• APS,^[22]
• BCR,^[23]
• CD63,^[24]
• CD81,^[24]
• CD9,^[24]
• CRK,^[25]
• CRKL,^[26][27]
• DOK1,^[28]
• FES,^[29]
• GRB10,^[30]
• Grb2,^[31][32][33]
• KITLG,^[34][35]
• LNK,^[36]
• LYN,^[28][37]
• MATK,^[38][39]
• MPDZ,^[40]
• PIK3R1,^[26][31][41]
• PTPN11,^[42][43]
• PTPN6,^[43][44]
• STAT1,^[45]
• SOCS1,^[31]
• SOCS6,^[46]
• SRC,^[47] and
• TEC.^[48]

See also

• Cytokine receptor
• List of genes mutated in pigmented cutaneous lesions

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000005672 - Ensembl, May 2017
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20. KTN0182A, an Anti-KIT, Pyrrolobenzodiazepine (PBD)-Containing Antibody Drug Conjugate (ADC) Demonstrates Potent Antitumor Activity In Vitro and In Vivo Against a Broad Range of Tumor Types; Lubeski C, Kemp GC, Von Bulow CL, Howard PW, Hartley JA, Douville T, Wellbrock J, et al.; 11th Annual PEGS - The Essential Protein Engineering Summit, Boston, 2015 October 30, 2015, at the Wayback Machine
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43. Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA (April 1998). "SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain". Molecular and Cellular Biology. 18 (4): 2089–2099. doi:10.1128/MCB.18.4.2089. PMC 121439. PMID 9528781.
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46. Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P (March 2004). "Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling". The Journal of Biological Chemistry. 279 (13): 12249–12259. doi:10.1074/jbc.M313381200. PMID 14707129.
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48. Tang B, Mano H, Yi T, Ihle JN (December 1994). "Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding". Molecular and Cellular Biology. 14 (12): 8432–8437. doi:10.1128/MCB.14.12.8432. PMC 359382. PMID 7526158.

Further reading

• Lennartsson J, Rönnstrand L (October 2012). "Stem cell factor receptor/c-Kit: from basic science to clinical implications". Physiological Reviews. 92 (4): 1619–1649. doi:10.1152/physrev.00046.2011. PMID 23073628.
• Lennartsson J, Rönnstrand L (February 2006). "The stem cell factor receptor/c-Kit as a drug target in cancer". Current Cancer Drug Targets. 6 (1): 65–75. doi:10.2174/156800906775471725. PMID 16475976.
• Rönnstrand L (October 2004). "Signal transduction via the stem cell factor receptor/c-Kit". Cellular and Molecular Life Sciences. 61 (19–20): 2535–2548. doi:10.1007/s00018-004-4189-6. PMID 15526160. S2CID 2602233.
• Linnekin D (October 1999). "Early signaling pathways activated by c-Kit in hematopoietic cells". The International Journal of Biochemistry & Cell Biology. 31 (10): 1053–1074. doi:10.1016/S1357-2725(99)00078-3. PMID 10582339.
• Canonico B, Felici C, Papa S (2001). "CD117". Journal of Biological Regulators and Homeostatic Agents. 15 (1): 90–94. PMID 11388751.
• Gupta R, Bain BJ, Knight CL (2002). "Cytogenetic and molecular genetic abnormalities in systemic mastocytosis". Acta Haematologica. 107 (2): 123–128. doi:10.1159/000046642. PMID 11919394. S2CID 20552257.
• Valent P, Ghannadan M, Hauswirth AW, Schernthaner GH, Sperr WR, Arock M (May 2002). "Signal transduction-associated and cell activation-linked antigens expressed in human mast cells". International Journal of Hematology. 75 (4): 357–362. doi:10.1007/BF02982124. PMID 12041664. S2CID 23033596.
• Sandberg AA, Bridge JA (May 2002). "Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors". Cancer Genetics and Cytogenetics. 135 (1): 1–22. doi:10.1016/S0165-4608(02)00546-0. PMID 12072198.
• Kitamura Y, Hirotab S (December 2004). "Kit as a human oncogenic tyrosine kinase". Cellular and Molecular Life Sciences. 61 (23): 2924–2931. doi:10.1007/s00018-004-4273-y. PMID 15583854.
• Larizza L, Magnani I, Beghini A (February 2005). "The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia". Leukemia & Lymphoma. 46 (2): 247–255. doi:10.1080/10428190400007565. PMID 15621809. S2CID 36086764.
• Miettinen M, Lasota J (September 2005). "KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation". Applied Immunohistochemistry & Molecular Morphology. 13 (3): 205–220. doi:10.1097/01.pai.0000173054.83414.22. PMID 16082245. S2CID 6912266.
• Lasota J, Miettinen M (May 2006). "KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)". Seminars in Diagnostic Pathology. 23 (2): 91–102. doi:10.1053/j.semdp.2006.08.006. PMID 17193822.
• Patnaik MM, Tefferi A, Pardanani A (August 2007). "Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders". Current Cancer Drug Targets. 7 (5): 492–503. doi:10.2174/156800907781386614. PMID 17691909.
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External links

• Proto-Oncogene+Proteins+c-kit at the US National Library of Medicine Medical Subject Headings (MeSH)
• C-kit receptor entry in the public domain NCI Dictionary of Cancer Terms
• Human KIT genome location and KIT gene details page in the UCSC Genome Browser.