KIT (gene) explained

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).^[1] Multiple transcript variants encoding different isoforms have been found for this gene.^{[2] [3]} KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.^[4]

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.^[5] 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.^[6] 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.^[7]

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.^{[8] [6] [9]}

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.^[10] 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.^[11]

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.^[12]

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.^[2]

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.

Anti-KIT therapies

KIT is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.^[13] 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.^[14] 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 Avapritinib or 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.^[15] 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.^[15]

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.^[16]

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.^[17]

Interactions

KIT has been shown to interact with:

• APS,^[18]
• BCR,^[19]
• CD63,
• CD81,
• CD9,^[20]
• CRK,^[21]
• CRKL,^{[22] [23]}
• DOK1,
• FES,^[24]
• GRB10,^[25]
• Grb2,^{[26] [27]}
• KITLG,^{[28] [29]}
• LNK,^[30]
• LYN,^{[31] [32]}
• MATK,^{[33] [34]}
• MPDZ,^[35]
• PIK3R1,^{[22] [36]}
• PTPN11,^{[37] [38]}
• PTPN6,^{[38] [39]}
• STAT1,^[40]
• SOCS1,^[41]
• SOCS6,^[42]
• SRC,^[43] and
• TEC.^[44]

See also

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

Further reading

• Lennartsson J, Rönnstrand L . Stem cell factor receptor/c-Kit: from basic science to clinical implications . Physiological Reviews . 92 . 4 . 1619–1649 . October 2012 . 23073628 . 10.1152/physrev.00046.2011 .
• Lennartsson J, Rönnstrand L . The stem cell factor receptor/c-Kit as a drug target in cancer . Current Cancer Drug Targets . 6 . 1 . 65–75 . February 2006 . 16475976 . 10.2174/156800906775471725 .
• Rönnstrand L . Signal transduction via the stem cell factor receptor/c-Kit . Cellular and Molecular Life Sciences . 61 . 19–20 . 2535–2548 . October 2004 . 15526160 . 10.1007/s00018-004-4189-6 . 2602233 .
• Linnekin D . Early signaling pathways activated by c-Kit in hematopoietic cells . The International Journal of Biochemistry & Cell Biology . 31 . 10 . 1053–1074 . October 1999 . 10582339 . 10.1016/S1357-2725(99)00078-3 .
• Canonico B, Felici C, Papa S . CD117 . Journal of Biological Regulators and Homeostatic Agents . 15 . 1 . 90–94 . 2001 . 11388751 .
• Gupta R, Bain BJ, Knight CL . Cytogenetic and molecular genetic abnormalities in systemic mastocytosis . Acta Haematologica . 107 . 2 . 123–128 . 2002 . 11919394 . 10.1159/000046642 . 20552257 .
• Valent P, Ghannadan M, Hauswirth AW, Schernthaner GH, Sperr WR, Arock M . Signal transduction-associated and cell activation-linked antigens expressed in human mast cells . International Journal of Hematology . 75 . 4 . 357–362 . May 2002 . 12041664 . 10.1007/BF02982124 . 23033596 .
• Sandberg AA, Bridge JA . Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors . Cancer Genetics and Cytogenetics . 135 . 1 . 1–22 . May 2002 . 12072198 . 10.1016/S0165-4608(02)00546-0 .
• Kitamura Y, Hirotab S . Kit as a human oncogenic tyrosine kinase . Cellular and Molecular Life Sciences . 61 . 23 . 2924–2931 . December 2004 . 15583854 . 10.1007/s00018-004-4273-y .
• Larizza L, Magnani I, Beghini A . The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia . Leukemia & Lymphoma . 46 . 2 . 247–255 . February 2005 . 15621809 . 10.1080/10428190400007565 . 36086764 .
• Miettinen M, Lasota J . 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 . September 2005 . 16082245 . 10.1097/01.pai.0000173054.83414.22 . 6912266 .
• Lasota J, Miettinen M . KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs) . Seminars in Diagnostic Pathology . 23 . 2 . 91–102 . May 2006 . 17193822 . 10.1053/j.semdp.2006.08.006 .
• Patnaik MM, Tefferi A, Pardanani A . Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders . Current Cancer Drug Targets . 7 . 5 . 492–503 . August 2007 . 17691909 . 10.2174/156800907781386614 .
• Giebel LB, Strunk KM, Holmes SA, Spritz RA . Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene . Oncogene . 7 . 11 . 2207–2217 . November 1992 . 1279499 .
• Spritz RA, Droetto S, Fukushima Y . Deletion of the KIT and PDGFRA genes in a patient with piebaldism . American Journal of Medical Genetics . 44 . 4 . 492–495 . November 1992 . 1279971 . 10.1002/ajmg.1320440422 .
• Spritz RA, Giebel LB, Holmes SA . 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 . February 1992 . 1370874 . 1682440 .
• Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW . 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 . March 1992 . 1371879 . 48497 . 10.1073/pnas.89.5.1587 . free . 1992PNAS...89.1587D .
• André C, Martin E, Cornu F, Hu WX, Wang XP, Galibert F . Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III . Oncogene . 7 . 4 . 685–691 . April 1992 . 1373482 .
• Lev S, Yarden Y, Givol D . 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 . May 1992 . 1375232 . 10.1016/S0021-9258(19)50098-9 . free .
• Fleischman RA . 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 . June 1992 . 1376329 . 295855 . 10.1172/JCI115772 .
• Vandenbark GR, deCastro CM, Taylor H, Dew-Knight S, Kaufman RE . Cloning and structural analysis of the human c-kit gene . Oncogene . 7 . 7 . 1259–1266 . July 1992 . 1377810 .
• Alai M, Mui AL, Cutler RL, Bustelo XR, Barbacid M, Krystal G . 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 . September 1992 . 1381360 . 10.1016/S0021-9258(19)37146-7 . free .
• Ashman LK, Cambareri AC, To LB, Levinsky RJ, Juttner CA . Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow . Blood . 78 . 1 . 30–37 . July 1991 . 1712644 . 10.1182/blood.V78.1.30.30 . free .

External links

• • C-kit receptor entry in the public domain NCI Dictionary of Cancer Terms

Notes and References

1. Andre C, Hampe A, Lachaume P, Martin E, Wang XP, Manus V, Hu WX, Galibert F . Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes . Genomics . 39 . 2 . 216–226 . January 1997 . 9027509 . 10.1006/geno.1996.4482 .
2. Web site: Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog.
3. National Cancer Institute Dictionary of Cancer Terms. c-kit. Accessed October 13, 2014.
4. Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A . Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand . The EMBO Journal . 6 . 11 . 3341–3351 . November 1987 . 2448137 . 553789 . 10.1002/j.1460-2075.1987.tb02655.x .
5. Edling CE, Hallberg B . c-Kit--a hematopoietic cell essential receptor tyrosine kinase . The International Journal of Biochemistry & Cell Biology . 39 . 11 . 1995–1998 . 2007 . 17350321 . 10.1016/j.biocel.2006.12.005 .
6. Blume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Heldin CH . Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis . The EMBO Journal . 10 . 13 . 4121–4128 . December 1991 . 1721869 . 453162 . 10.1002/j.1460-2075.1991.tb04989.x .
7. Studies of genetic variability at the KIT locus and white spotting patterns in the horse . Brooks S . 2006 . University of Kentucky Doctoral Dissertations . 13–16.
8. Roskoski R . Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor . Biochemical and Biophysical Research Communications . 338 . 3 . 1307–1315 . December 2005 . 16226710 . 10.1016/j.bbrc.2005.09.150 .
9. Haase B, Brooks SA, Schlumbaum A, Azor PJ, Bailey E, Alaeddine F, Mevissen M, Burger D, Poncet PA, Rieder S, Leeb T . Allelic heterogeneity at the equine KIT locus in dominant white (W) horses . PLOS Genetics . 3 . 11 . e195 . November 2007 . 17997609 . 2065884 . 10.1371/journal.pgen.0030195 . free .
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12. Sheikh E, Tran T, Vranic S, Levy A, Bonfil RD . Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review . Bosnian Journal of Basic Medical Sciences . April 2022 . 22 . 5 . 683–698 . 35490363 . 10.17305/bjbms.2021.7399 . 9519160 .
13. Web site: KIT . 2008-03-01 . Jean-Loup Huret . Atlas of Genetics and Cytogenetics in Oncology and Haematology.
14. 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 . 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 . September 2005 . 16166280 . 10.1158/0008-5472.CAN-05-0471 . free .
15. Purohit R . 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 . 2014 . 23782055 . 10.1080/07391102.2013.803264 . 5528573 .
16. http://www.kolltan.com/news/kolltan-pharmaceuticals-to-present-at-the-11th-annual-pegs-the-essential-protein-engineering-summit/ 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
17. Book: Leong AS, Cooper K, Leong FJ . 2003. Manual of Diagnostic Cytology. 2. Greenwich Medical Media, Ltd.. 149–151. 978-1-84110-100-2.
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22. van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M . Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells . Blood . 96 . 10 . 3406–3413 . November 2000 . 11071635 . 10.1182/blood.V96.10.3406 . 1765/9530 . free .
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29. Blechman JM, Lev S, Brizzi MF, Leitner O, Pegoraro L, Givol D, Yarden Y . Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor . The Journal of Biological Chemistry . 268 . 6 . 4399–4406 . February 1993 . 7680037 . 10.1016/S0021-9258(18)53623-1 . free .
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32. Linnekin D, DeBerry CS, Mou S . 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 . October 1997 . 9341198 . 10.1074/jbc.272.43.27450 . free .
33. Jhun BH, Rivnay B, Price D, Avraham H . The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit . The Journal of Biological Chemistry . 270 . 16 . 9661–9666 . April 1995 . 7536744 . 10.1074/jbc.270.16.9661 . free .
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35. Mancini A, Koch A, Stefan M, Niemann H, Tamura T . 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 . September 2000 . 11018522 . 10.1016/S0014-5793(00)02036-6 . 40159587 .
36. Serve H, Hsu YC, Besmer P . 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 . February 1994 . 7509796 . 10.1016/S0021-9258(17)37564-6 . free .
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39. Yi T, Ihle JN . Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand . Molecular and Cellular Biology . 13 . 6 . 3350–3358 . June 1993 . 7684496 . 359793 . 10.1128/MCB.13.6.3350 .
40. Deberry C, Mou S, Linnekin D . Stat1 associates with c-kit and is activated in response to stem cell factor . The Biochemical Journal . 327 . 1 . 73–80 . October 1997 . 9355737 . 1218765 . 10.1042/bj3270073 .
41. De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R . Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation . The EMBO Journal . 18 . 4 . 904–915 . February 1999 . 10022833 . 1171183 . 10.1093/emboj/18.4.904 .
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43. Lennartsson J, Blume-Jensen P, Hermanson M, Pontén E, Carlberg M, Rönnstrand L . 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 . September 1999 . 10523831 . 10.1038/sj.onc.1202929 . free .
44. Tang B, Mano H, Yi T, Ihle JN . 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 . December 1994 . 7526158 . 359382 . 10.1128/MCB.14.12.8432 .