KIT (gene)

KIT
Available structures
PDBOrtholog search: PDBe RCSB
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
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: 75.57 – 75.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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 (a substance that causes certain types of cells to grow), 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]

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]

Anti-KIT therapies

KIT is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.[16] 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.[17] 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.[18] 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.[18]

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.[19]

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.[20]

Interactions

KIT has been shown to interact with:

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000157404 - Ensembl, May 2017
  2. 1 2 3 GRCm38: 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, Hu WX, Galibert F (January 1997). "Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes". Genomics. 39 (2): 216–26. doi:10.1006/geno.1996.4482. PMID 9027509.
  6. 1 2 "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, Chen E, Schlessinger J, Francke U, Ullrich A (November 1987). "Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand". EMBO J. 6 (11): 3341–51. doi:10.1002/j.1460-2075.1987.tb02655.x. PMC 553789. PMID 2448137.
  9. ↑ Edling CE, Hallberg B (2007). "c-Kit--a hematopoietic cell essential receptor tyrosine kinase". Int. J. Biochem. Cell Biol. 39 (11): 1995–8. doi:10.1016/j.biocel.2006.12.005. PMID 17350321.
  10. 1 2 Blume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Heldin CH (1991-12-10). "Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis". EMBO Journal. 10 (13): 4121–4128. doi:10.1002/j.1460-2075.1991.tb04989.x. PMC 453162. PMID 1721869.
  11. ↑ Brooks, Samantha (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 (2005-12-23). "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. PMID 16226710.
  13. ↑ Haase B, Brooks SA, Schlumbaum A, 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. PMC 2065884. PMID 17997609.
  14. ↑ Leong KG, Wang BE, Johnson L, Gao WQ (October 2008). "Generation of a prostate from a single adult stem cell". Nature. 456 (7223): 804–8. Bibcode:2008Natur.456..804L. doi:10.1038/nature07427. PMID 18946470. S2CID 4410656.
  15. ↑ Vallentin, B.; Barlogis, V.; Piperoglou, C.; Cypowyj, S.; Zucchini, N.; Chene, M.; Navarro, F.; Farnarier, C.; Vivier, E.; Vely, F. (4 October 2015). "Innate Lymphoid Cells in Cancer". Cancer Immunology Research. 3 (10): 1109–1114. doi:10.1158/2326-6066.CIR-15-0222. PMID 26438443.
  16. ↑ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-01.
  17. ↑ McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, Dennis N, Fisher C, Huddart R, Cooper C, Clark J, Oosterhuis JW, Looijenga LH, Shipley J (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 Res. 65 (18): 8085–9. doi:10.1158/0008-5472.CAN-05-0471. PMID 16166280.
  18. 1 2 Purohit 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): 1033–46. doi:10.1080/07391102.2013.803264. PMID 23782055. S2CID 5528573.
  19. ↑ 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 Archived October 30, 2015, at the Wayback Machine
  20. ↑ Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 149–151. ISBN 978-1-84110-100-2.
  21. ↑ 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". Biochem. J. 370 (Pt 3): 1033–8. doi:10.1042/BJ20020716. PMC 1223215. PMID 12444928.
  22. ↑ Hallek M, Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, Druker B, Griffin JD, Emmerich B, Ullrich A (July 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". Br. J. Haematol. 94 (1): 5–16. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502. S2CID 30033345.
  23. 1 2 3 Anzai N, Lee Y, Youn BS, Fukuda S, Kim YJ, Mantel C, Akashi M, Broxmeyer HE (June 2002). "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors". Blood. 99 (12): 4413–21. doi:10.1182/blood.V99.12.4413. PMID 12036870.
  24. ↑ 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". Exp. Cell Res. 288 (1): 110–8. doi:10.1016/S0014-4827(03)00206-4. PMID 12878163.
  25. 1 2 van 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): 3406–13. doi:10.1182/blood.V96.10.3406. PMID 11071635.
  26. ↑ Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD (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)". J. Biol. Chem. 272 (15): 10248–53. doi:10.1074/jbc.272.15.10248. PMID 9092574.
  27. 1 2 Liang 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". J. Biol. Chem. 277 (16): 13732–8. doi:10.1074/jbc.M200277200. PMID 11825908.
  28. ↑ Voisset E, Lopez S, Chaix A, Vita M, George C, Dubreuil P, De Sepulveda P (February 2010). "FES kinase participates in KIT-ligand induced chemotaxis". Biochem. Biophys. Res. Commun. 393 (1): 174–8. doi:10.1016/j.bbrc.2010.01.116. PMID 20117079.
  29. ↑ Jahn T, Seipel P, Urschel S, Peschel C, Duyster J (February 2002). "Role for the adaptor protein Grb10 in the activation of Akt". Mol. Cell. Biol. 22 (4): 979–91. doi:10.1128/MCB.22.4.979-991.2002. PMC 134632. PMID 11809791.
  30. 1 2 3 De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R (February 1999). "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". EMBO J. 18 (4): 904–15. doi:10.1093/emboj/18.4.904. PMC 1171183. PMID 10022833.
  31. ↑ 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". Biochem. J. 341 (1): 211–6. doi:10.1042/0264-6021:3410211. PMC 1220349. PMID 10377264.
  32. ↑ 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". J. Biol. Chem. 271 (21): 12129–32. doi:10.1074/jbc.271.21.12129. PMID 8647802.
  33. ↑ 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". J. Biol. Chem. 267 (15): 10866–73. doi:10.1016/S0021-9258(19)50098-9. PMID 1375232.
  34. ↑ Blechman JM, Lev S, Brizzi MF, Leitner O, Pegoraro L, Givol D, Yarden Y (February 1993). "Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor". J. Biol. Chem. 268 (6): 4399–406. doi:10.1016/S0021-9258(18)53623-1. PMID 7680037.
  35. ↑ Gueller S, Gery S, Nowak V, Liu L, Serve H, Koeffler HP (October 2008). "Adaptor protein Lnk associates with Tyr(568) in c-Kit". Biochem. J. 415 (2): 241–5. doi:10.1042/BJ20080102. PMID 18588518.
  36. ↑ 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". J. Biol. Chem. 272 (43): 27450–5. doi:10.1074/jbc.272.43.27450. PMID 9341198.
  37. ↑ 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". J. Biol. Chem. 270 (16): 9661–6. doi:10.1074/jbc.270.16.9661. PMID 7536744.
  38. ↑ 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". J. Biol. Chem. 272 (9): 5915–20. doi:10.1074/jbc.272.9.5915. PMID 9038210.
  39. ↑ 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 Lett. 482 (1–2): 54–8. doi:10.1016/S0014-5793(00)02036-6. PMID 11018522. S2CID 40159587.
  40. ↑ 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". J. Biol. Chem. 269 (8): 6026–30. doi:10.1016/S0021-9258(17)37564-6. PMID 7509796.
  41. ↑ Tauchi T, Feng GS, Marshall MS, Shen R, Mantel C, Pawson T, Broxmeyer HE (October 1994). "The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells". J. Biol. Chem. 269 (40): 25206–11. doi:10.1016/S0021-9258(17)31518-1. PMID 7523381.
  42. 1 2 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". Mol. Cell. Biol. 18 (4): 2089–99. doi:10.1128/MCB.18.4.2089. PMC 121439. PMID 9528781.
  43. ↑ Yi T, Ihle JN (June 1993). "Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand". Mol. Cell. Biol. 13 (6): 3350–8. doi:10.1128/MCB.13.6.3350. PMC 359793. PMID 7684496.
  44. ↑ Deberry C, Mou S, Linnekin D (October 1997). "Stat1 associates with c-kit and is activated in response to stem cell factor". Biochem. J. 327 (1): 73–80. doi:10.1042/bj3270073. PMC 1218765. PMID 9355737.
  45. ↑ 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". J. Biol. Chem. 279 (13): 12249–59. doi:10.1074/jbc.M313381200. PMID 14707129.
  46. ↑ 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): 5546–53. doi:10.1038/sj.onc.1202929. PMID 10523831.
  47. ↑ 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". Mol. Cell. Biol. 14 (12): 8432–7. doi:10.1128/MCB.14.12.8432. PMC 359382. PMID 7526158.

Further reading

  • 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.
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