KIT (gene)
Proto-oncogene c-KITis the gene encoding thereceptor tyrosine kinaseprotein known astyrosine-protein kinase KIT,CD117(cluster of differentiation117) 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]
Function
[edit]KIT is acytokine receptorexpressed on the surface ofhematopoietic stem cellsas well as other cell types. Altered forms of this receptor may be associated with some types ofcancer.[9]KIT is areceptor tyrosine kinasetype 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 adimerthat 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 alysosomeand eventual destruction. Signaling through KIT plays a role in cell survival, proliferation, and differentiation. For instance, KIT signaling is required formelanocytesurvival, and it is also involved inhaematopoiesisandgametogenesis.[11]
Structure
[edit]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 factorbinds via the second and third immunoglobulin domains.[12][10][13]
Cell surface marker
[edit]Cluster of differentiation(CD) molecules are markers on the cell surface, as recognized by specific sets ofantibodies,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 ofhematopoietic(blood) progenitors in thebone marrow.To be specific,hematopoietic stem cells(HSC),multipotent progenitors(MPP), andcommon myeloid progenitors(CMP) express high levels of KIT.Common lymphoid progenitors(CLP) express low surface levels of KIT. KIT also identifies the earliestthymocyteprogenitors in thethymus—early T lineage progenitors (ETP/DN1) and DN2 thymocytes express high levels of c-Kit. It is also a marker for mouseprostatestem cells.[14]In addition,mast cells,melanocytesin the skin, andinterstitial cells of Cajalin thedigestive tractexpress 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
[edit]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-CSFis 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 KITagonistsare currently being developed as mobilization agents.
Role in cancer
[edit]Activating mutations in this gene are associated withgastrointestinal stromal tumors,testicularseminoma,mast cell disease,melanoma,acute myeloid leukemia,while inactivating mutations are associated with the genetic defectpiebaldism.[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
[edit]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 asdasatinibAvapritinib ornilotinibcan 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)-containingantibody-drug conjugatewhich shows anti-tumor activityin vitroandin vivoagainst a range of tumor types.[20]
Diagnostic relevance
[edit]Antibodies to KIT are widely used inimmunohistochemistryto help distinguish particular types of tumour inhistologicaltissue sections. It is used primarily in the diagnosis of GISTs, which are positive for KIT, but negative for markers such asdesminandS-100,which are positive insmooth muscleand 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 tumoursand in distinguishingseminomasfromembryonal carcinomas.[21]
Interactions
[edit]KIT has been shown tointeractwith:
See also
[edit]References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000157404–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000005672–Ensembl,May 2017
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- ^ab"Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog".
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- ^Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, et al. (April 1997)."Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL)".The Journal of Biological Chemistry.272(15): 10248–10253.doi:10.1074/jbc.272.15.10248.PMID9092574.
- ^abLiang X, Wisniewski D, Strife A, Clarkson B, Resh MD (April 2002)."Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling".The Journal of Biological Chemistry.277(16): 13732–13738.doi:10.1074/jbc.M200277200.PMID11825908.
- ^Voisset E, Lopez S, Chaix A, Vita M, George C, Dubreuil P, et al. (February 2010). "FES kinase participates in KIT-ligand induced chemotaxis".Biochemical and Biophysical Research Communications.393(1): 174–178.doi:10.1016/j.bbrc.2010.01.116.PMID20117079.
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- ^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.PMID14707129.
- ^Lennartsson J, Blume-Jensen P, Hermanson M, Pontén E, Carlberg M, Rönnstrand L (September 1999)."Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction".Oncogene.18(40): 5546–5553.doi:10.1038/sj.onc.1202929.PMID10523831.
- ^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.PMC359382.PMID7526158.
Further reading
[edit]- 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.PMID23073628.
- 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.PMID16475976.
- 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.PMID15526160.S2CID2602233.
- 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.PMID10582339.
- Canonico B, Felici C, Papa S (2001). "CD117".Journal of Biological Regulators and Homeostatic Agents.15(1): 90–94.PMID11388751.
- 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.PMID11919394.S2CID20552257.
- 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.PMID12041664.S2CID23033596.
- 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.PMID12072198.
- 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.PMID15583854.
- 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.PMID15621809.S2CID36086764.
- 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.PMID16082245.S2CID6912266.
- 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.PMID17193822.
- 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.PMID17691909.
- Giebel LB, Strunk KM, Holmes SA, Spritz RA (November 1992). "Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene".Oncogene.7(11): 2207–2217.PMID1279499.
- Spritz RA, Droetto S, Fukushima Y (November 1992). "Deletion of the KIT and PDGFRA genes in a patient with piebaldism".American Journal of Medical Genetics.44(4): 492–495.doi:10.1002/ajmg.1320440422.PMID1279971.
- Spritz RA, Giebel LB, Holmes SA (February 1992)."Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism".American Journal of Human Genetics.50(2): 261–269.PMC1682440.PMID1370874.
- Duronio V,Welham MJ,Abraham S, Dryden P, Schrader JW (March 1992)."p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein".Proceedings of the National Academy of Sciences of the United States of America.89(5): 1587–1591.Bibcode:1992PNAS...89.1587D.doi:10.1073/pnas.89.5.1587.PMC48497.PMID1371879.
- André C, Martin E, Cornu F, Hu WX, Wang XP, Galibert F (April 1992). "Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III".Oncogene.7(4): 685–691.PMID1373482.
- Lev S, Yarden Y, Givol D (May 1992)."A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses".The Journal of Biological Chemistry.267(15): 10866–10873.doi:10.1016/S0021-9258(19)50098-9.PMID1375232.
- Fleischman RA (June 1992)."Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene".The Journal of Clinical Investigation.89(6): 1713–1717.doi:10.1172/JCI115772.PMC295855.PMID1376329.
- Vandenbark GR, deCastro CM, Taylor H, Dew-Knight S, Kaufman RE (July 1992). "Cloning and structural analysis of the human c-kit gene".Oncogene.7(7): 1259–1266.PMID1377810.
- Alai M, Mui AL, Cutler RL, Bustelo XR, Barbacid M, Krystal G (September 1992)."Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells".The Journal of Biological Chemistry.267(25): 18021–18025.doi:10.1016/S0021-9258(19)37146-7.PMID1381360.
- Ashman LK, Cambareri AC, To LB, Levinsky RJ, Juttner CA (July 1991)."Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow".Blood.78(1): 30–37.doi:10.1182/blood.V78.1.30.30.PMID1712644.
External links
[edit]- Proto-Oncogene+Proteins+c-kitat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- C-kit receptorentry in the public domain NCI Dictionary of Cancer Terms
- HumanKITgenome location andKITgene details page in theUCSC Genome Browser.