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KIT (gene)

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KIT
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesKIT,C-Kit, CD117, PBT, SCFR, KIT proto-oncogene receptor tyrosine kinase, MASTC, KIT proto-oncogene, receptor tyrosine kinase
External IDsOMIM:164920;MGI:96677;HomoloGene:187;GeneCards:KIT;OMA:KIT - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 5: 75.74 – 75.82 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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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

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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

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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

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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

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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

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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

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KIT has been shown tointeractwith:

See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000157404–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000005672–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Andre C, Hampe A, Lachaume P, Martin E, Wang XP, Manus V, et al. (January 1997). "Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes".Genomics.39(2): 216–226.doi:10.1006/geno.1996.4482.PMID9027509.
  6. ^ab"Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog".
  7. ^National Cancer Institute Dictionary of Cancer Terms.c-kit.Accessed October 13, 2014.
  8. ^Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, et al. (November 1987)."Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand".The EMBO Journal.6(11): 3341–3351.doi:10.1002/j.1460-2075.1987.tb02655.x.PMC553789.PMID2448137.
  9. ^Edling CE, Hallberg B (2007). "c-Kit--a hematopoietic cell essential receptor tyrosine kinase".The International Journal of Biochemistry & Cell Biology.39(11): 1995–1998.doi:10.1016/j.biocel.2006.12.005.PMID17350321.
  10. ^abBlume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Heldin CH (December 1991)."Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis".The EMBO Journal.10(13): 4121–4128.doi:10.1002/j.1460-2075.1991.tb04989.x.PMC453162.PMID1721869.
  11. ^Brooks S (2006).Studies of genetic variability at the KIT locus and white spotting patterns in the horse(Thesis). University of Kentucky Doctoral Dissertations. pp. 13–16.
  12. ^Roskoski R (December 2005). "Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor".Biochemical and Biophysical Research Communications.338(3): 1307–1315.doi:10.1016/j.bbrc.2005.09.150.PMID16226710.
  13. ^Haase B, Brooks SA, Schlumbaum A, Azor PJ, Bailey E, Alaeddine F, et al. (November 2007)."Allelic heterogeneity at the equine KIT locus in dominant white (W) horses".PLOS Genetics.3(11): e195.doi:10.1371/journal.pgen.0030195.PMC2065884.PMID17997609.
  14. ^Leong KG, Wang BE, Johnson L, Gao WQ (December 2008). "Generation of a prostate from a single adult stem cell".Nature.456(7223): 804–808.Bibcode:2008Natur.456..804L.doi:10.1038/nature07427.PMID18946470.S2CID4410656.
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  16. ^abSheikh E, Tran T, Vranic S, Levy A, Bonfil RD (April 2022)."Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review".Bosnian Journal of Basic Medical Sciences.22(5): 683–698.doi:10.17305/bjbms.2021.7399.PMC9519160.PMID35490363.
  17. ^Jean-Loup Huret."KIT".Atlas of Genetics and Cytogenetics in Oncology and Haematology.Retrieved2008-03-01.
  18. ^McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, et al. (September 2005)."Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults".Cancer Research.65(18): 8085–8089.doi:10.1158/0008-5472.CAN-05-0471.PMID16166280.
  19. ^abPurohit R (2014)."Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight".Journal of Biomolecular Structure & Dynamics.32(7): 1033–1046.doi:10.1080/07391102.2013.803264.PMID23782055.S2CID5528573.
  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, 2015ArchivedOctober 30, 2015, at theWayback Machine
  21. ^Leong AS, Cooper K, Leong FJ (2003).Manual of Diagnostic Cytology(2 ed.). Greenwich Medical Media, Ltd. pp. 149–151.ISBN978-1-84110-100-2.
  22. ^Wollberg P, Lennartsson J, Gottfridsson E, Yoshimura A, Rönnstrand L (March 2003)."The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit".The Biochemical Journal.370(Pt 3): 1033–1038.doi:10.1042/BJ20020716.PMC1223215.PMID12444928.
  23. ^Hallek M, Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, et al. (July 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells".British Journal of Haematology.94(1): 5–16.doi:10.1046/j.1365-2141.1996.6102053.x.PMID8757502.S2CID30033345.
  24. ^abcAnzai N, Lee Y, Youn BS, Fukuda S, Kim YJ, Mantel C, et al. (June 2002). "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors".Blood.99(12): 4413–4421.doi:10.1182/blood.V99.12.4413.PMID12036870.
  25. ^Lennartsson J, Wernstedt C, Engström U, Hellman U, Rönnstrand L (August 2003). "Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk".Experimental Cell Research.288(1): 110–118.doi:10.1016/S0014-4827(03)00206-4.PMID12878163.
  26. ^abvan Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M (November 2000)."Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells".Blood.96(10): 3406–3413.doi:10.1182/blood.V96.10.3406.hdl:1765/9530.PMID11071635.
  27. ^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.
  28. ^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.
  29. ^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.
  30. ^Jahn T, Seipel P, Urschel S, Peschel C, Duyster J (February 2002)."Role for the adaptor protein Grb10 in the activation of Akt".Molecular and Cellular Biology.22(4): 979–991.doi:10.1128/MCB.22.4.979-991.2002.PMC134632.PMID11809791.
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  32. ^Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L (July 1999)."Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor".The Biochemical Journal.341(1): 211–216.doi:10.1042/0264-6021:3410211.PMC1220349.PMID10377264.
  33. ^Feng GS, Ouyang YB, Hu DP, Shi ZQ, Gentz R, Ni J (May 1996)."Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway".The Journal of Biological Chemistry.271(21): 12129–12132.doi:10.1074/jbc.271.21.12129.PMID8647802.
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  37. ^Linnekin D, DeBerry CS, Mou S (October 1997)."Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells".The Journal of Biological Chemistry.272(43): 27450–27455.doi:10.1074/jbc.272.43.27450.PMID9341198.
  38. ^Jhun BH, Rivnay B, Price D, Avraham H (April 1995)."The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit".The Journal of Biological Chemistry.270(16): 9661–9666.doi:10.1074/jbc.270.16.9661.PMID7536744.
  39. ^Price DJ, Rivnay B, Fu Y, Jiang S, Avraham S, Avraham H (February 1997)."Direct association of Csk homologous kinase (CHK) with the diphosphorylated site Tyr568/570 of the activated c-KIT in megakaryocytes".The Journal of Biological Chemistry.272(9): 5915–5920.doi:10.1074/jbc.272.9.5915.PMID9038210.
  40. ^Mancini A, Koch A, Stefan M, Niemann H, Tamura T (September 2000). "The direct association of the multiple PDZ domain containing proteins (MUPP-1) with the human c-Kit C-terminus is regulated by tyrosine kinase activity".FEBS Letters.482(1–2): 54–58.doi:10.1016/S0014-5793(00)02036-6.PMID11018522.S2CID40159587.
  41. ^Serve H, Hsu YC, Besmer P (February 1994)."Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells".The Journal of Biological Chemistry.269(8): 6026–6030.doi:10.1016/S0021-9258(17)37564-6.PMID7509796.
  42. ^Tauchi T, Feng GS, Marshall MS, Shen R, Mantel C, Pawson T, et al. (October 1994)."The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells".The Journal of Biological Chemistry.269(40): 25206–25211.doi:10.1016/S0021-9258(17)31518-1.PMID7523381.
  43. ^abKozlowski 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.PMC121439.PMID9528781.
  44. ^Yi T, Ihle JN (June 1993)."Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand".Molecular and Cellular Biology.13(6): 3350–3358.doi:10.1128/MCB.13.6.3350.PMC359793.PMID7684496.
  45. ^Deberry C, Mou S, Linnekin D (October 1997)."Stat1 associates with c-kit and is activated in response to stem cell factor".The Biochemical Journal.327(1): 73–80.doi:10.1042/bj3270073.PMC1218765.PMID9355737.
  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.PMID14707129.
  47. ^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.
  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.PMC359382.PMID7526158.

Further reading

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