Biology:KIT (gene)

From HandWiki
Revision as of 00:52, 11 February 2024 by Smart bot editor (talk | contribs) (correction)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Short description: Mammalian protein and protein-coding gene


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[12]

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:


See also

References

  1. ↑ "Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes". Genomics 39 (2): 216–226. January 1997. doi:10.1006/geno.1996.4482. PMID 9027509. 
  2. ↑ 2.0 2.1 "Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3815. 
  3. ↑ National Cancer Institute Dictionary of Cancer Terms. c-kit. Accessed October 13, 2014.
  4. ↑ "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. doi:10.1002/j.1460-2075.1987.tb02655.x. PMID 2448137. 
  5. ↑ "c-Kit--a hematopoietic cell essential receptor tyrosine kinase". The International Journal of Biochemistry & Cell Biology 39 (11): 1995–1998. 2007. doi:10.1016/j.biocel.2006.12.005. PMID 17350321. 
  6. ↑ 6.0 6.1 "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. doi:10.1002/j.1460-2075.1991.tb04989.x. PMID 1721869. 
  7. ↑ 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.
  8. ↑ "Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor". Biochemical and Biophysical Research Communications 338 (3): 1307–1315. December 2005. doi:10.1016/j.bbrc.2005.09.150. PMID 16226710. 
  9. ↑ "Allelic heterogeneity at the equine KIT locus in dominant white (W) horses". PLOS Genetics 3 (11): e195. November 2007. doi:10.1371/journal.pgen.0030195. PMID 17997609. 
  10. ↑ "Generation of a prostate from a single adult stem cell". Nature 456 (7223): 804–808. December 2008. doi:10.1038/nature07427. PMID 18946470. Bibcode: 2008Natur.456..804L. 
  11. ↑ "Innate Lymphoid Cells in Cancer". Cancer Immunology Research 3 (10): 1109–1114. October 2015. doi:10.1158/2326-6066.CIR-15-0222. PMID 26438443. 
  12. ↑ 12.0 12.1 "Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review". Bosnian Journal of Basic Medical Sciences 22 (5): 683–698. April 2022. doi:10.17305/bjbms.2021.7399. PMID 35490363. 
  13. ↑ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. http://AtlasGeneticsOncology.org/Genes/KITID127.html. 
  14. ↑ "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. doi:10.1158/0008-5472.CAN-05-0471. PMID 16166280. 
  15. ↑ 15.0 15.1 "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. doi:10.1080/07391102.2013.803264. PMID 23782055. https://figshare.com/articles/dataset/Role_of_ELA_region_in_auto_activation_of_mutant_KIT_receptor_a_molecular_dynamics_simulation_insight/825934. 
  16. ↑ 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. ↑ Leong, Anthony S-Y; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd.. pp. 149–151. ISBN 978-1-84110-100-2. 
  18. ↑ "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. March 2003. doi:10.1042/BJ20020716. PMID 12444928. 
  19. ↑ "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". British Journal of Haematology 94 (1): 5–16. July 1996. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502. 
  20. ↑ 20.0 20.1 20.2 "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors". Blood 99 (12): 4413–4421. June 2002. doi:10.1182/blood.V99.12.4413. PMID 12036870. 
  21. ↑ "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. August 2003. doi:10.1016/S0014-4827(03)00206-4. PMID 12878163. 
  22. ↑ 22.0 22.1 "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood 96 (10): 3406–3413. November 2000. doi:10.1182/blood.V96.10.3406. PMID 11071635. https://pure.eur.nl/en/publications/395fb5fc-60e3-45d7-a9b1-fc7b9cc6b4bc. 
  23. ↑ "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. April 1997. doi:10.1074/jbc.272.15.10248. PMID 9092574. 
  24. ↑ 24.0 24.1 "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. April 2002. doi:10.1074/jbc.M200277200. PMID 11825908. 
  25. ↑ "FES kinase participates in KIT-ligand induced chemotaxis". Biochemical and Biophysical Research Communications 393 (1): 174–178. February 2010. doi:10.1016/j.bbrc.2010.01.116. PMID 20117079. 
  26. ↑ "Role for the adaptor protein Grb10 in the activation of Akt". Molecular and Cellular Biology 22 (4): 979–991. February 2002. doi:10.1128/MCB.22.4.979-991.2002. PMID 11809791. 
  27. ↑ 27.0 27.1 27.2 "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". The EMBO Journal 18 (4): 904–915. February 1999. doi:10.1093/emboj/18.4.904. PMID 10022833. 
  28. ↑ "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. July 1999. doi:10.1042/0264-6021:3410211. PMID 10377264. 
  29. ↑ "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. May 1996. doi:10.1074/jbc.271.21.12129. PMID 8647802. 
  30. ↑ "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. doi:10.1016/S0021-9258(19)50098-9. PMID 1375232. 
  31. ↑ "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. doi:10.1016/S0021-9258(18)53623-1. PMID 7680037. 
  32. ↑ "Adaptor protein Lnk associates with Tyr(568) in c-Kit". The Biochemical Journal 415 (2): 241–245. October 2008. doi:10.1042/BJ20080102. PMID 18588518. https://hal.science/hal-00478952/file/PEER_stage2_10.1042%252FBJ20080102.pdf. 
  33. ↑ "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. doi:10.1074/jbc.272.43.27450. PMID 9341198. 
  34. ↑ "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. doi:10.1074/jbc.270.16.9661. PMID 7536744. 
  35. ↑ "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. February 1997. doi:10.1074/jbc.272.9.5915. PMID 9038210. 
  36. ↑ "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. doi:10.1016/S0014-5793(00)02036-6. PMID 11018522. 
  37. ↑ "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. doi:10.1016/S0021-9258(17)37564-6. PMID 7509796. 
  38. ↑ "The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells". The Journal of Biological Chemistry 269 (40): 25206–25211. October 1994. doi:10.1016/S0021-9258(17)31518-1. PMID 7523381. 
  39. ↑ 39.0 39.1 "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. April 1998. doi:10.1128/MCB.18.4.2089. PMID 9528781. 
  40. ↑ "Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand". Molecular and Cellular Biology 13 (6): 3350–3358. June 1993. doi:10.1128/MCB.13.6.3350. PMID 7684496. 
  41. ↑ "Stat1 associates with c-kit and is activated in response to stem cell factor". The Biochemical Journal 327 (1): 73–80. October 1997. doi:10.1042/bj3270073. PMID 9355737. 
  42. ↑ "Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling". The Journal of Biological Chemistry 279 (13): 12249–12259. March 2004. doi:10.1074/jbc.M313381200. PMID 14707129. 
  43. ↑ "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. doi:10.1038/sj.onc.1202929. PMID 10523831. 
  44. ↑ "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. doi:10.1128/MCB.14.12.8432. PMID 7526158. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:KIT_(gene)&oldid=3536788"