KIT (gene)
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 4: 54.66 – 54.74 Mb | Chr 5: 75.74 – 75.82 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/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 , 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
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
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
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.[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,
Diagnostic relevance
Antibodies to KIT are widely used in
Interactions
KIT has been shown to
See also
- Cytokine receptor
- List of genes mutated in pigmented cutaneous lesions
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000157404 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005672 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9027509.
- ^ a b "Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog".
- ^ National Cancer Institute Dictionary of Cancer Terms. c-kit. Accessed October 13, 2014.
- PMID 2448137.
- PMID 17350321.
- ^ PMID 1721869.
- ^ 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.
- PMID 16226710.
- PMID 17997609.
- S2CID 4410656.
- PMID 26438443.
- ^ PMID 35490363.
- ^ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-01.
- PMID 16166280.
- ^ S2CID 5528573.
- ^ 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
- ISBN 978-1-84110-100-2.
- PMID 12444928.
- S2CID 30033345.
- ^ PMID 12036870.
- PMID 12878163.
- ^ PMID 11071635.
- PMID 9092574.
- ^ PMID 11825908.
- PMID 20117079.
- PMID 11809791.
- ^ PMID 10022833.
- PMID 10377264.
- PMID 8647802.
- PMID 1375232.
- PMID 7680037.
- S2CID 39310714.
- PMID 9341198.
- PMID 7536744.
- PMID 9038210.
- S2CID 40159587.
- PMID 7509796.
- PMID 7523381.
- ^ PMID 9528781.
- PMID 7684496.
- PMID 9355737.
- PMID 14707129.
- PMID 10523831.
- 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. 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. 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. 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. 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. 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. 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. PMID 12072198.
- Kitamura Y, Hirotab S (December 2004). "Kit as a human oncogenic tyrosine kinase". Cellular and Molecular Life Sciences. 61 (23): 2924–2931. 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. 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. 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. 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. PMID 17691909.
- 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. PMID 1279499.
- 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. PMID 1279971.
- 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. PMID 1370874.
- Duronio V, PMID 1371879.
- 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. PMID 1373482.
- 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. PMID 1375232.
- 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. PMID 1376329.
- 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. PMID 1377810.
- 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. PMID 1381360.
- 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. PMID 1712644.
External links
- Proto-Oncogene+Proteins+c-kit at the U.S. 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.
PDB gallery | |
|---|---|
|
