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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox gene}}
{{PBB_Controls
'''Mast/stem cell growth factor receptor''' ('''SCFR'''), also known as '''proto-oncogene c-Kit''' or '''tyrosine-protein kinase Kit''' or '''CD117''', is a [[receptor tyrosine kinase]] [[protein]] that in humans is encoded by the '''''KIT''''' [[gene]].<ref name="pmid9027509">{{cite journal | vauthors = Andre C, Hampe A, Lachaume P, Martin E, Wang XP, Manus V, Hu WX, Galibert F | title = Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes | journal = Genomics | volume = 39 | issue = 2 | pages = 216–26 | date = January 1997 | pmid = 9027509 | doi = 10.1006/geno.1996.4482 }}</ref> Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3815| accessdate = }}</ref><ref>National Cancer Institute Dictionary of Cancer Terms. [http://www.cancer.gov/dictionary?cdrid=44329 c-kit]. Accessed October 13, 2014.</ref>
| update_page = yes
KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.<ref name="pmid2448137">{{cite journal | vauthors = Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A | title = Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand | journal = EMBO J. | volume = 6 | issue = 11 | pages = 3341–51 | date = November 1987 | pmid = 2448137 | pmc = 553789 | doi =  }}</ref>
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_KIT_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1pkg.
| PDB = {{PDB2|1pkg}}, {{PDB2|1t45}}, {{PDB2|1t46}}
| Name = V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
| HGNCid = 6342
| Symbol = KIT
| AltSymbols =; C-Kit; CD117; SCFR
| OMIM = 164920
| ECnumber = 
| Homologene = 187
| MGIid = 96677
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004716 |text = receptor signaling protein tyrosine kinase activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005020 |text = stem cell factor receptor activity}} {{GNF_GO|id=GO:0005021 |text = vascular endothelial growth factor receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0009897 |text = external side of plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006470 |text = protein amino acid dephosphorylation}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007169 |text = transmembrane receptor protein tyrosine kinase signaling pathway}} {{GNF_GO|id=GO:0007243 |text = protein kinase cascade}} {{GNF_GO|id=GO:0009314 |text = response to radiation}} {{GNF_GO|id=GO:0018108 |text = peptidyl-tyrosine phosphorylation}} {{GNF_GO|id=GO:0019221 |text = cytokine and chemokine mediated signaling pathway}} {{GNF_GO|id=GO:0030097 |text = hemopoiesis}} {{GNF_GO|id=GO:0048066 |text = pigmentation during development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3815
    | Hs_Ensembl =
    | Hs_RefseqProtein = NP_000213
    | Hs_RefseqmRNA = NM_000222
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr =
    | Hs_GenLoc_start =   
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 16590
    | Mm_Ensembl = ENSMUSG00000005672
    | Mm_RefseqmRNA = NM_021099
    | Mm_RefseqProtein = NP_066922
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 75856705
    | Mm_GenLoc_end = 75938416
    | Mm_Uniprot = Q3ULJ6
  }}
}}
{{CMG}}


==Overview==
== Cell surface marker ==
'''CD117''', also called '''KIT''' or '''C-kit receptor''', is a [[cytokine receptor]] expressed on the surface of [[hematopoietic stem cell]]s as well as other cell types. This receptor binds to [[stem cell factor]] (a substance that causes certain types of cells to grow). [[Altered]] forms of this receptor may be [[associated]] with some types of [[cancer]].<ref name="pmid17350321">{{cite journal | author = Edling CE, Hallberg B | title = c-Kit--a hematopoietic cell essential receptor tyrosine kinase | journal = Int. J. Biochem. Cell Biol. | volume = 39 | issue = 11 | pages = 1995–8 | year = 2007 | pmid = 17350321 | doi = 10.1016/j.biocel.2006.12.005 | issn = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
[[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. CD117 is an important cell surface marker used to identify certain types of [[hematopoietic]] (blood) progenitors in the [[bone marrow]]. To be specific, [[hematopoietic stem cell]]s (HSC), [[multipotent progenitor]]s (MPP), and [[common myeloid progenitor]]s (CMP) express high levels of CD117. [[Common lymphoid progenitor]]s (CLP) express low surface levels of CD117.  
{{PBB_Summary
CD117 also identifies the earliest [[thymocyte]] progenitors in the [[thymus]]. To be specific, early T lineage progenitors (ETP/DN1) and DN2 thymocytes express high levels of c-Kit. It is also a marker for mouse [[prostate]] [[stem cell]]s.<ref name="pmid18946470">{{cite journal | vauthors = Leong KG, Wang BE, Johnson L, Gao WQ | title = Generation of a prostate from a single adult stem cell | journal = Nature | volume = 456 | issue = 7223 | pages = 804–8 | date = October 2008 | pmid = 18946470 | doi = 10.1038/nature07427 }}</ref> In addition, [[mast cells]], [[melanocytes]] in the skin, and [[interstitial cells of Cajal]] in the [[digestive tract]] express CD117. 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.<ref>{{cite journal|last1=Vallentin|first1=B.|last2=Barlogis|first2=V.|last3=Piperoglou|first3=C.|last4=Cypowyj|first4=S.|last5=Zucchini|first5=N.|last6=Chene|first6=M.|last7=Navarro|first7=F.|last8=Farnarier|first8=C.|last9=Vivier|first9=E.|last10=Vely|first10=F.|title=Innate Lymphoid Cells in Cancer|journal=Cancer Immunology Research|date=4 October 2015|volume=3|issue=10|pages=1109–1114|doi=10.1158/2326-6066.CIR-15-0222|pmid=26438443|url=http://cancerimmunolres.aacrjournals.org/content/3/10/1109}}</ref>
| section_title =
| summary_text = This gene encodes the human homolog of the proto-oncogene c-kit. C-kit was first identified as the cellular homolog of the feline sarcoma viral oncogene v-kit. This protein is a type 3 transmembrane receptor for MGF (mast cell growth factor, also known as stem cell factor). Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous lukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3815| accessdate = }}</ref>
}}


==Cell Surface Marker==
== Function ==
[[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. CD117 is an important cell surface marker used to identify certain types of [[hematopoietic]] (blood) progenitors in the [[bone marrow]]. Specifically hematopoietic stem cells (HSC), multipotent progenitors (MPP), and common myeloid progenitors (CMP) express high levels of CD117. Common lymphoid progenitors (CLP) expresses low surface levels of CD117.


CD117 also identifies the earliest [[thymocyte]] progenitors in the [[thymus]]. Specifically early T lineage progenitors (ETP/DN1) and DN2 thymocytes express high levels of c-Kit.
CD117 is a [[cytokine receptor]] expressed on the surface of [[hematopoietic stem cell]]s as well as other cell types. Altered forms of this receptor may be associated with some types of [[cancer]].<ref name="pmid17350321">{{cite journal | vauthors = Edling CE, Hallberg B | title = c-Kit--a hematopoietic cell essential receptor tyrosine kinase | journal = Int. J. Biochem. Cell Biol. | volume = 39 | issue = 11 | pages = 1995–8 | year = 2007 | pmid = 17350321 | doi = 10.1016/j.biocel.2006.12.005 }}</ref> CD117 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 [[protein dimer|dimer]] that activates its intrinsic tyrosine kinase activity, that in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation.


Additionally [[mast cells]], [[melanocytes]] in the skin, and [[interstitial cells of Cajal]] in the [[digestive tract]] express CD117.
== Mobilization ==


==Ligand==
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 CD117 has been implicated in mobilization. At the current time, [[G-CSF]] is the main drug used for mobilization; it indirectly activates CD117. [[Plerixafor]] (an antagonist of [[CXCR4-SDF1]]) in combination with G-CSF, is also being used for mobilization of hematopoietic progenitor cells. Direct CD117 [[agonists]] are currently being developed as mobilization agents.
CD117 is the receptor for the [[cytokine]] [[stem cell factor]] (SCF), also known as "steel factor" or "c-kit ligand". SCF exists in two forms, cell surface bound SCF and soluble (or free) SCF.


==Function==
== Role in cancer ==
CD117 is a [[receptor tyrosine kinase]] type III. When this receptor binds to SCF it forms a [[dimer]] which activates signaling through [[second messengers]]. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation.


==Mobilization==
Activating mutations in this gene are associated with [[gastrointestinal stromal tumor]]s, testicular [[seminoma]], mast cell disease, [[melanoma]], [[acute myeloid leukemia]], while inactivating mutations are associated with the genetic defect [[piebaldism]].<ref name="entrez"/>
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 CD117 has been implicated in mobilization. Currently, [[G-CSF]] is the main drug used for mobilization. G-CSF indirectly activates CD117. Direct CD117 [[agonists]] are currently being developed as mobilization agents.


==Role in cancer==
===Anti-KIT therapies===
CD117 is a [[proto-oncogene]], meaning that overexpression or mutations of this protein can lead to cancer.<ref name="titleKIT">{{cite web | url = http://AtlasGeneticsOncology.org/Genes/KITID127.html | title = KIT | accessdate = 2008-03-01 | author = Jean-Loup Huret | authorlink = | coauthors = | date = | format = | work = | publisher = Atlas of Genetics and Cytogenetics in Oncology and Haematology| pages = | language = | archiveurl = | archivedate = | quote = }}</ref>  Seminomas, a subtype of testicular [[germ cell tumors]], frequently have activating mutations in exon 17 of CD117.  In addition, the gene encoding CD117 is frequently overexpressed and amplified in this tumour type, most commonly occurring as a single gene amplicon.<ref name="pmid16166280">{{cite journal | author = 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 | title = Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults | journal = Cancer Res. | volume = 65 | issue = 18 | pages = 8085–9 | year = 2005 | pmid = 16166280 | doi = 10.1158/0008-5472.CAN-05-0471 | issn = }}</ref> Mutations of CD117 have also been implicated in [[leukemia]], a cancer of hematopoietic progenitors, and [[gastrointestinal stromal tumor]]s (GISTs).  The efficacy of [[imatinib]], a CD117 inhibitor, is determined by the mutation status of CD117.


==See also==
CD117 is a [[proto-oncogene]], meaning that overexpression or mutations of this protein can lead to cancer.<ref name="titleKIT">{{cite web | url = http://AtlasGeneticsOncology.org/Genes/KITID127.html | title = KIT | accessdate = 2008-03-01 | author = Jean-Loup Huret | authorlink = | coauthors = | date = | work = | publisher = Atlas of Genetics and Cytogenetics in Oncology and Haematology| pages = | quote = }}</ref>  Seminomas, a subtype of testicular [[germ cell tumors]], frequently have activating mutations in exon 17 of CD117.  In addition, the gene encoding CD117 is frequently overexpressed and amplified in this tumor type, most commonly occurring as a [[single gene amplicon]].<ref name="pmid16166280">{{cite journal | vauthors = 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 | title = Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults | journal = Cancer Res. | volume = 65 | issue = 18 | pages = 8085–9 | year = 2005 | pmid = 16166280 | doi = 10.1158/0008-5472.CAN-05-0471 }}</ref> Mutations of CD117 have also been implicated in [[leukemia]], a cancer of hematopoietic progenitors, [[melanoma]], mast cell disease, and [[gastrointestinal stromal tumor]]s (GISTs). The efficacy of [[imatinib]] (trade name Gleevec), a CD117 inhibitor, is determined by the mutation status of CD117:
* [[Cluster of differentiation]]
* [[cytokine receptor]]
* [[receptor tyrosine kinase]]
* [[tyrosine kinase]]
* [[oncogene]]
* [[hematopoiesis]]


==References==
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.<ref name="pmid23782055">{{cite journal | vauthors = Purohit R | title = Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight | journal = Journal of Biomolecular Structure & Dynamics | volume = 32 | issue = 7 | pages = 1033–46 | year = 2014 | pmid = 23782055 | doi = 10.1080/07391102.2013.803264 }}</ref> 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.<ref name="pmid23782055"/>
{{reflist|2}}


==Further reading==
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.<ref>[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] {{webarchive |url=https://web.archive.org/web/20151030025033/http://www.kolltan.com/news/kolltan-pharmaceuticals-to-present-at-the-11th-annual-pegs-the-essential-protein-engineering-summit/ |date=October 30, 2015 }}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
== Diagnostic relevance ==
| citations =
 
*{{cite journal  | author=Linnekin D |title=Early signaling pathways activated by c-Kit in hematopoietic cells. |journal=Int. J. Biochem. Cell Biol. |volume=31 |issue= 10 |pages= 1053-74 |year= 2000 |pmid= 10582339 |doi=  }}
Antibodies to CD117 are widely used in [[immunohistochemistry]] to help distinguish particular types of tumour in [[histology|histological]] tissue sections. It is used primarily in the diagnosis of GISTs, which are positive for CD117, but negative for markers such as [[desmin]] and [[S-100 protein|S-100]], which are positive in [[leiomyosarcoma|smooth muscle]] and neural tumors, which have a similar appearance. In GISTs, CD117 staining is typically [[cytoplasm]]ic, with stronger accentuation along the [[cell membrane]]s. CD117 antibodies can also be used in the diagnosis of [[mast cell tumour]]s and in distinguishing [[seminoma]]s from [[embryonal carcinoma]]s.<ref name=Leong>{{cite book|author=Leong, Anthony S-Y|author2=Cooper, Kumarason|author3=Leong, F Joel W-M|year=2003|title=Manual of Diagnostic Cytology|edition=2|publisher=Greenwich Medical Media, Ltd.|pages=149–151|isbn=1-84110-100-1}}</ref>
*{{cite journal  | author=Canonico B, Felici C, Papa S |title=CD117. |journal=J. Biol. Regul. Homeost. Agents |volume=15 |issue= 1 |pages= 90-4 |year= 2001 |pmid= 11388751 |doi=  }}
 
*{{cite journal  | author=Gupta R, Bain BJ, Knight CL |title=Cytogenetic and molecular genetic abnormalities in systemic mastocytosis. |journal=Acta Haematol. |volume=107 |issue= 2 |pages= 123-8 |year= 2002 |pmid= 11919394 |doi= }}
== Interactions ==
*{{cite journal  | author=Valent P, Ghannadan M, Hauswirth AW, ''et al.'' |title=Signal transduction-associated and cell activation-linked antigens expressed in human mast cells. |journal=Int. J. Hematol. |volume=75 |issue= 4 |pages= 357-62 |year= 2003 |pmid= 12041664 |doi=  }}
 
*{{cite journal | author=Sandberg AA, Bridge JA |title=Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors. |journal=Cancer Genet. Cytogenet. |volume=135 |issue= 1 |pages= 1-22 |year= 2002 |pmid= 12072198 |doi= }}
CD117 has been shown to [[Protein-protein interaction|interact]] with:
*{{cite journal | author=Kitamura Y, Hirotab S |title=Kit as a human oncogenic tyrosine kinase. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 23 |pages= 2924-31 |year= 2005 |pmid= 15583854 |doi= 10.1007/s00018-004-4273-y }}
{{div col|colwidth=15em}}
*{{cite journal | author=Larizza L, Magnani I, Beghini A |title=The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. |journal=Leuk. Lymphoma |volume=46 |issue= 2 |pages= 247-55 |year= 2005 |pmid= 15621809 |doi= 10.1080/10428190400007565 }}
* [[SH2B2|APS]],<ref name="pmid12444928">{{cite journal | vauthors = Wollberg P, Lennartsson J, Gottfridsson E, Yoshimura A, Rönnstrand L | title = The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit | journal = Biochem. J. | volume = 370 | issue = Pt 3 | pages = 1033–8 | date = March 2003 | pmid = 12444928 | pmc = 1223215 | doi = 10.1042/BJ20020716 }}</ref>
*{{cite journal | author=Miettinen M, Lasota J |title=KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. |journal=Appl. Immunohistochem. Mol. Morphol. |volume=13 |issue= 3 |pages= 205-20 |year= 2006 |pmid= 16082245 |doi= }}
* [[BCR gene|BCR]],<ref name="pmid8757502">{{cite journal | vauthors = Hallek M, Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, Druker B, Griffin JD, Emmerich B, Ullrich A | title = Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells | journal = Br. J. Haematol. | volume = 94 | issue = 1 | pages = 5–16 | date = July 1996 | pmid = 8757502 | doi = 10.1046/j.1365-2141.1996.6102053.x }}</ref>
*{{cite journal | author=Lasota J, Miettinen M |title=KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). |journal=Semin Diagn Pathol |volume=23 |issue= 2 |pages= 91-102 |year= 2007 |pmid= 17193822 |doi=  }}
* [[CD63]],<ref name=pmid12036870/>
*{{cite journal | author=Patnaik MM, Tefferi A, Pardanani A |title=Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders. |journal=Current cancer drug targets |volume=7 |issue= 5 |pages= 492-503 |year= 2007 |pmid= 17691909 |doi= }}
* [[CD81]],<ref name=pmid12036870/>
*{{cite journal | author=Giebel LB, Strunk KM, Holmes SA, Spritz RA |title=Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. |journal=Oncogene |volume=7 |issue= 11 |pages= 2207-17 |year= 1992 |pmid= 1279499 |doi= }}
* [[CD9]],<ref name="pmid12036870">{{cite journal | vauthors = Anzai N, Lee Y, Youn BS, Fukuda S, Kim YJ, Mantel C, Akashi M, Broxmeyer HE | title = C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors | journal = Blood | volume = 99 | issue = 12 | pages = 4413–21 | date = June 2002 | pmid = 12036870 | doi = 10.1182/blood.V99.12.4413 }}</ref>
*{{cite journal | author=Spritz RA, Droetto S, Fukushima Y |title=Deletion of the KIT and PDGFRA genes in a patient with piebaldism. |journal=Am. J. Med. Genet. |volume=44 |issue= 4 |pages= 492-5 |year= 1992 |pmid= 1279971 |doi= 10.1002/ajmg.1320440422 }}
* [[CRK (gene)|CRK]],<ref name=pmid12878163/><ref name="pmid12878163">{{cite journal | vauthors = Lennartsson J, Wernstedt C, Engström U, Hellman U, Rönnstrand L | title = Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk | journal = Exp. Cell Res. | volume = 288 | issue = 1 | pages = 110–8 | date = August 2003 | pmid = 12878163 | doi = 10.1016/S0014-4827(03)00206-4 }}</ref>
*{{cite journal | author=Spritz RA, Giebel LB, Holmes SA |title=Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. |journal=Am. J. Hum. Genet. |volume=50 |issue= 2 |pages= 261-9 |year= 1992 |pmid= 1370874 |doi= }}
* [[CRKL]],<ref name="pmid11071635">{{cite journal | vauthors = van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M | title = Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells | journal = Blood | volume = 96 | issue = 10 | pages = 3406–13 | date = November 2000 | pmid = 11071635 | doi =  }}</ref><ref name="pmid9092574">{{cite journal | vauthors = Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD | title = Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL) | journal = J. Biol. Chem. | volume = 272 | issue = 15 | pages = 10248–53 | date = April 1997 | pmid = 9092574 | doi = 10.1074/jbc.272.15.10248 }}</ref>
*{{cite journal | author=Duronio V, Welham MJ, Abraham S, ''et al.'' |title=p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 5 |pages= 1587-91 |year= 1992 |pmid= 1371879 |doi= }}
* [[DOK1]],<ref name=pmid11825908/>
*{{cite journal | author=André C, Martin E, Cornu F, ''et al.'' |title=Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III. |journal=Oncogene |volume=7 |issue= 4 |pages= 685-91 |year= 1992 |pmid= 1373482 |doi=  }}
* [[Feline sarcoma oncogene|FES]],<ref name=pmid20117079/><ref name="pmid20117079">{{cite journal | vauthors = Voisset E, Lopez S, Chaix A, Vita M, George C, Dubreuil P, De Sepulveda P | title = FES kinase participates in KIT-ligand induced chemotaxis | journal = Biochem. Biophys. Res. Commun. | volume = 393 | issue = 1 | pages = 174–8 | date = February 2010 | pmid = 20117079 | doi = 10.1016/j.bbrc.2010.01.116 }}</ref>
*{{cite journal | author=Lev S, Yarden Y, Givol D |title=A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. |journal=J. Biol. Chem. |volume=267 |issue= 15 |pages= 10866-73 |year= 1992 |pmid= 1375232 |doi=  }}
* [[GRB10]],<ref name="pmid11809791">{{cite journal | vauthors = Jahn T, Seipel P, Urschel S, Peschel C, Duyster J | title = Role for the adaptor protein Grb10 in the activation of Akt | journal = Mol. Cell. Biol. | volume = 22 | issue = 4 | pages = 979–91 | date = February 2002 | pmid = 11809791 | pmc = 134632 | doi = 10.1128/MCB.22.4.979-991.2002 }}</ref>
*{{cite journal | author=Fleischman RA |title=Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene. |journal=J. Clin. Invest. |volume=89 |issue= 6 |pages= 1713-7 |year= 1992 |pmid= 1376329 |doi= }}
* [[Grb2]],<ref name=pmid10022833/><ref name="pmid10377264">{{cite journal | vauthors = Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L | title = Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor | journal = Biochem. J. | volume = 341 | issue = 1 | pages = 211–6 | date = July 1999 | pmid = 10377264 | pmc = 1220349 | doi = 10.1042/0264-6021:3410211 }}</ref><ref name="pmid8647802">{{cite journal | vauthors = Feng GS, Ouyang YB, Hu DP, Shi ZQ, Gentz R, Ni J | title = Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway | journal = J. Biol. Chem. | volume = 271 | issue = 21 | pages = 12129–32 | date = May 1996 | pmid = 8647802 | doi = 10.1074/jbc.271.21.12129 }}</ref>
*{{cite journal | author=Vandenbark GR, deCastro CM, Taylor H, ''et al.'' |title=Cloning and structural analysis of the human c-kit gene. |journal=Oncogene |volume=7 |issue= 7 |pages= 1259-66 |year= 1992 |pmid= 1377810 |doi= }}
* [[Stem cell factor|KITLG]],<ref name="pmid1375232">{{cite journal | vauthors = Lev S, Yarden Y, Givol D | title = A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses | journal = J. Biol. Chem. | volume = 267 | issue = 15 | pages = 10866–73 | date = May 1992 | pmid = 1375232 | doi =  }}</ref><ref name="pmid7680037">{{cite journal | vauthors = Blechman JM, Lev S, Brizzi MF, Leitner O, Pegoraro L, Givol D, Yarden Y | title = Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor | journal = J. Biol. Chem. | volume = 268 | issue = 6 | pages = 4399–406 | date = February 1993 | pmid = 7680037 | doi =  }}</ref>
*{{cite journal | author=Alai M, Mui AL, Cutler RL, ''et al.'' |title=Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells. |journal=J. Biol. Chem. |volume=267 |issue= 25 |pages= 18021-5 |year= 1992 |pmid= 1381360 |doi= }}
* [[SH2B3|LNK]],<ref name="pmid18588518">{{cite journal | vauthors = Gueller S, Gery S, Nowak V, Liu L, Serve H, Koeffler HP | title = Adaptor protein Lnk associates with Tyr(568) in c-Kit | journal = Biochem. J. | volume = 415 | issue = 2 | pages = 241–5 | date = October 2008 | pmid = 18588518 | doi = 10.1042/BJ20080102 }}</ref>
*{{cite journal  | author=Ashman LK, Cambareri AC, To LB, ''et al.'' |title=Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow. |journal=Blood |volume=78 |issue= 1 |pages= 30-7 |year= 1991 |pmid= 1712644 |doi=  }}
* [[LYN]],<ref name="pmid11825908">{{cite journal | vauthors = Liang X, Wisniewski D, Strife A, Clarkson B, Resh MD | title = Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling | journal = J. Biol. Chem. | volume = 277 | issue = 16 | pages = 13732–8 | date = April 2002 | pmid = 11825908 | doi = 10.1074/jbc.M200277200 }}</ref><ref name="pmid9341198">{{cite journal | vauthors = Linnekin D, DeBerry CS, Mou S | title = Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells | journal = J. Biol. Chem. | volume = 272 | issue = 43 | pages = 27450–5 | date = October 1997 | pmid = 9341198 | doi = 10.1074/jbc.272.43.27450 }}</ref>
}}
* [[Megakaryocyte-associated tyrosine kinase|MATK]],<ref name="pmid7536744">{{cite journal | vauthors = Jhun BH, Rivnay B, Price D, Avraham H | title = The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit | journal = J. Biol. Chem. | volume = 270 | issue = 16 | pages = 9661–6 | date = April 1995 | pmid = 7536744 | doi = 10.1074/jbc.270.16.9661 }}</ref><ref name="pmid9038210">{{cite journal | vauthors = Price DJ, Rivnay B, Fu Y, Jiang S, Avraham S, Avraham H | title = Direct association of Csk homologous kinase (CHK) with the diphosphorylated site Tyr568/570 of the activated c-KIT in megakaryocytes | journal = J. Biol. Chem. | volume = 272 | issue = 9 | pages = 5915–20 | date = February 1997 | pmid = 9038210 | doi = 10.1074/jbc.272.9.5915 }}</ref>
* [[MPDZ]],<ref name="pmid11018522">{{cite journal | vauthors = Mancini A, Koch A, Stefan M, Niemann H, Tamura T | title = 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 | journal = FEBS Lett. | volume = 482 | issue = 1–2 | pages = 54–8 | date = September 2000 | pmid = 11018522 | doi = 10.1016/S0014-5793(00)02036-6 }}</ref>
* [[PIK3R1]],<ref name=pmid11071635/><ref name=pmid10022833/><ref name="pmid7509796">{{cite journal | vauthors = Serve H, Hsu YC, Besmer P | title = 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 | journal = J. Biol. Chem. | volume = 269 | issue = 8 | pages = 6026–30 | date = February 1994 | pmid = 7509796 | doi =  }}</ref>
* [[PTPN11]],<ref name="pmid7523381">{{cite journal | vauthors = Tauchi T, Feng GS, Marshall MS, Shen R, Mantel C, Pawson T, Broxmeyer HE | title = The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells | journal = J. Biol. Chem. | volume = 269 | issue = 40 | pages = 25206–11 | date = October 1994 | pmid = 7523381 | doi =  }}</ref><ref name="pmid9528781">{{cite journal | vauthors = Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA | title = SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain | journal = Mol. Cell. Biol. | volume = 18 | issue = 4 | pages = 2089–99 | date = April 1998 | pmid = 9528781 | pmc = 121439 | doi =  }}</ref>
* [[PTPN6]],<ref name=pmid9528781/><ref name="pmid7684496">{{cite journal | vauthors = Yi T, Ihle JN | title = Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand | journal = Mol. Cell. Biol. | volume = 13 | issue = 6 | pages = 3350–8 | date = June 1993 | pmid = 7684496 | pmc = 359793 | doi =  }}</ref>
* [[STAT1]],<ref name="pmid9355737">{{cite journal | vauthors = Deberry C, Mou S, Linnekin D | title = Stat1 associates with c-kit and is activated in response to stem cell factor | journal = Biochem. J. | volume = 327 | issue = 1 | pages = 73–80 | date = October 1997 | pmid = 9355737 | pmc = 1218765 | doi =  10.1042/bj3270073}}</ref>
* [[Suppressor of cytokine signaling 1|SOCS1]],<ref name="pmid10022833">{{cite journal | vauthors = De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R | title = Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation | journal = EMBO J. | volume = 18 | issue = 4 | pages = 904–15 | date = February 1999 | pmid = 10022833 | pmc = 1171183 | doi = 10.1093/emboj/18.4.904 }}</ref>
* [[SOCS6]],<ref name="pmid14707129">{{cite journal | vauthors = Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P | title = Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling | journal = J. Biol. Chem. | volume = 279 | issue = 13 | pages = 12249–59 | date = March 2004 | pmid = 14707129 | doi = 10.1074/jbc.M313381200 }}</ref>
* [[Src (gene)|SRC]],<ref name="pmid10523831">{{cite journal | vauthors = Lennartsson J, Blume-Jensen P, Hermanson M, Pontén E, Carlberg M, Rönnstrand L | title = 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 | journal = Oncogene | volume = 18 | issue = 40 | pages = 5546–53 | date = September 1999 | pmid = 10523831 | doi = 10.1038/sj.onc.1202929 }}</ref> and
* [[TEC (gene)|TEC]].<ref name="pmid7526158">{{cite journal | vauthors = Tang B, Mano H, Yi T, Ihle JN | title = Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding | journal = Mol. Cell. Biol. | volume = 14 | issue = 12 | pages = 8432–7 | date = December 1994 | pmid = 7526158 | pmc = 359382 | doi =  }}</ref>
{{Div col end}}
 
== See also ==
* [[Cytokine receptor]]
* [[List of genes mutated in pigmented cutaneous lesions]]
 
== References ==
{{reflist|colwidth=35em}}
 
== Further reading ==
{{refbegin|colwidth=35em}}
* {{cite journal | vauthors = Lennartsson J, Rönnstrand L | title = Stem cell factor receptor/c-Kit: from basic science to clinical implications. | journal = Physiol. Rev. | volume = 92 | issue = 4 | pages = 1619–49 | year = 2012 | pmid = 23073628 | doi = 10.1152/physrev.00046.2011 }}
* {{cite journal | vauthors = Lennartsson J, Rönnstrand L | title = The stem cell factor receptor/c-Kit as a drug target in cancer | journal = Curr. Cancer Drug Targ. | volume = 6 | issue = 1 | pages = 65–75 | year = 2006 | pmid = 16475976 | doi = 10.2174/156800906775471725 }}
* {{cite journal | vauthors = Rönnstrand L | title = Signal transduction via the stem cell factor receptor/c-Kit | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 19–20 | pages = 2535–2548 | year = 2004 | pmid = 15526160 | doi = 10.1007/s00018-004-4189-6 }}
* {{cite journal | vauthors = Linnekin D | title = Early signaling pathways activated by c-Kit in hematopoietic cells | journal = Int. J. Biochem. Cell Biol. | volume = 31 | issue = 10 | pages = 1053–74 | year = 2000 | pmid = 10582339 | doi = 10.1016/S1357-2725(99)00078-3 }}
* {{cite journal | vauthors = Canonico B, Felici C, Papa S | title = CD117 | journal = J. Biol. Regul. Homeost. Agents | volume = 15 | issue = 1 | pages = 90–4 | year = 2001 | pmid = 11388751 | doi =  }}
* {{cite journal | vauthors = Gupta R, Bain BJ, Knight CL | title = Cytogenetic and molecular genetic abnormalities in systemic mastocytosis | journal = Acta Haematol. | volume = 107 | issue = 2 | pages = 123–8 | year = 2002 | pmid = 11919394 | doi = 10.1159/000046642 }}
* {{cite journal | vauthors = Valent P, Ghannadan M, Hauswirth AW, Schernthaner GH, Sperr WR, Arock M | title = Signal transduction-associated and cell activation-linked antigens expressed in human mast cells | journal = Int. J. Hematol. | volume = 75 | issue = 4 | pages = 357–62 | year = 2003 | pmid = 12041664 | doi = 10.1007/BF02982124 }}
* {{cite journal | vauthors = Sandberg AA, Bridge JA | title = Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors | journal = Cancer Genet. Cytogenet. | volume = 135 | issue = 1 | pages = 1–22 | year = 2002 | pmid = 12072198 | doi = 10.1016/S0165-4608(02)00546-0 }}
* {{cite journal | vauthors = Kitamura Y, Hirotab S | title = Kit as a human oncogenic tyrosine kinase | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 23 | pages = 2924–31 | year = 2005 | pmid = 15583854 | doi = 10.1007/s00018-004-4273-y }}
* {{cite journal | vauthors = Larizza L, Magnani I, Beghini A | title = The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia | journal = Leuk. Lymphoma | volume = 46 | issue = 2 | pages = 247–55 | year = 2005 | pmid = 15621809 | doi = 10.1080/10428190400007565 }}
* {{cite journal | vauthors = Miettinen M, Lasota J | title = KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation | journal = Appl. Immunohistochem. Mol. Morphol. | volume = 13 | issue = 3 | pages = 205–20 | year = 2006 | pmid = 16082245 | doi = 10.1097/01.pai.0000173054.83414.22 }}
* {{cite journal | vauthors = Lasota J, Miettinen M | title = KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs) | journal = Semin Diagn Pathol | volume = 23 | issue = 2 | pages = 91–102 | year = 2007 | pmid = 17193822 | doi = 10.1053/j.semdp.2006.08.006 }}
* {{cite journal | vauthors = Patnaik MM, Tefferi A, Pardanani A | title = Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders | journal = Current Cancer Drug Targets | volume = 7 | issue = 5 | pages = 492–503 | year = 2007 | pmid = 17691909 | doi = 10.2174/156800907781386614 }}
* {{cite journal | vauthors = Giebel LB, Strunk KM, Holmes SA, Spritz RA | title = Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene | journal = Oncogene | volume = 7 | issue = 11 | pages = 2207–17 | year = 1992 | pmid = 1279499 | doi =  }}
* {{cite journal | vauthors = Spritz RA, Droetto S, Fukushima Y | title = Deletion of the KIT and PDGFRA genes in a patient with piebaldism | journal = Am. J. Med. Genet. | volume = 44 | issue = 4 | pages = 492–5 | year = 1992 | pmid = 1279971 | doi = 10.1002/ajmg.1320440422 }}
* {{cite journal | vauthors = Spritz RA, Giebel LB, Holmes SA | title = Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism | journal = Am. J. Hum. Genet. | volume = 50 | issue = 2 | pages = 261–9 | year = 1992 | pmid = 1370874 | pmc = 1682440 | doi =  }}
* {{cite journal | vauthors = Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW | title = p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 5 | pages = 1587–91 | year = 1992 | pmid = 1371879 | pmc = 48497 | doi = 10.1073/pnas.89.5.1587 }}
* {{cite journal | vauthors = André C, Martin E, Cornu F, Hu WX, Wang XP, Galibert F | title = Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III | journal = Oncogene | volume = 7 | issue = 4 | pages = 685–91 | year = 1992 | pmid = 1373482 | doi =  }}
* {{cite journal | vauthors = Lev S, Yarden Y, Givol D | title = A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses | journal = J. Biol. Chem. | volume = 267 | issue = 15 | pages = 10866–73 | year = 1992 | pmid = 1375232 | doi =  }}
* {{cite journal | vauthors = Fleischman RA | title = Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene | journal = J. Clin. Invest. | volume = 89 | issue = 6 | pages = 1713–7 | year = 1992 | pmid = 1376329 | pmc = 295855 | doi = 10.1172/JCI115772 }}
* {{cite journal | vauthors = Vandenbark GR, deCastro CM, Taylor H, Dew-Knight S, Kaufman RE | title = Cloning and structural analysis of the human c-kit gene | journal = Oncogene | volume = 7 | issue = 7 | pages = 1259–66 | year = 1992 | pmid = 1377810 | doi =  }}
* {{cite journal | vauthors = Alai M, Mui AL, Cutler RL, Bustelo XR, Barbacid M, Krystal G | title = Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells | journal = J. Biol. Chem. | volume = 267 | issue = 25 | pages = 18021–5 | year = 1992 | pmid = 1381360 | doi =  }}
* {{cite journal | vauthors = Ashman LK, Cambareri AC, To LB, Levinsky RJ, Juttner CA | title = Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow | journal = Blood | volume = 78 | issue = 1 | pages = 30–7 | year = 1991 | pmid = 1712644 | doi =  }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Proto-Oncogene+Proteins+c-kit}}
* {{MeshName|Proto-Oncogene+Proteins+c-kit}}
* [http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44329 C-kit receptor] entry in the public domain NCI Dictionary of Cancer Terms
* [http://www.cancer.gov/dictionary?CdrID=44329 C-kit receptor] entry in the public domain NCI Dictionary of Cancer Terms
* {{UCSC gene info|KIT}}


{{PDB Gallery|geneid=3815}}
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{{Clusters of differentiation}}
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{{Growth factor receptors}}
{{Immune receptors}}
{{Cytokine receptors}}
{{Oncogenes}}
{{Oncogenes}}
{{Tyrosine kinases}}
{{Tyrosine kinases}}
{{Enzymes}}
{{Growth factor receptor modulators}}
{{Cytokine receptor modulators}}
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[[Category:Cytokine receptors]]
[[Category:Immunoglobulin superfamily cytokine receptors]]
[[Category:EC 2.7.10]]
[[Category:EC 2.7.10]]
[[Category:Tyrosine kinases]]
[[Category:Tyrosine kinase receptors]]
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Latest revision as of 11:59, 10 January 2019

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Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a receptor tyrosine kinase protein that in humans is encoded by the KIT gene.[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]

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. CD117 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 CD117. Common lymphoid progenitors (CLP) express low surface levels of CD117. CD117 also identifies the earliest thymocyte progenitors in the thymus. To be specific, 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.[5] In addition, mast cells, melanocytes in the skin, and interstitial cells of Cajal in the digestive tract express CD117. 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.[6]

Function

CD117 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.[7] CD117 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. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation.

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 CD117 has been implicated in mobilization. At the current time, G-CSF is the main drug used for mobilization; it indirectly activates CD117. Plerixafor (an antagonist of CXCR4-SDF1) in combination with G-CSF, is also being used for mobilization of hematopoietic progenitor cells. Direct CD117 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]

Anti-KIT therapies

CD117 is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.[8] Seminomas, a subtype of testicular germ cell tumors, frequently have activating mutations in exon 17 of CD117. In addition, the gene encoding CD117 is frequently overexpressed and amplified in this tumor type, most commonly occurring as a single gene amplicon.[9] Mutations of CD117 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 CD117 inhibitor, is determined by the mutation status of CD117:

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.[10] 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.[10]

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.[11]

Diagnostic relevance

Antibodies to CD117 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 CD117, 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, CD117 staining is typically cytoplasmic, with stronger accentuation along the cell membranes. CD117 antibodies can also be used in the diagnosis of mast cell tumours and in distinguishing seminomas from embryonal carcinomas.[12]

Interactions

CD117 has been shown to interact with:

See also

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 "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 (November 1987). "Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand". EMBO J. 6 (11): 3341–51. PMC 553789. PMID 2448137.
  5. ↑ 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. doi:10.1038/nature07427. PMID 18946470.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-01.
  9. ↑ 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.
  10. ↑ 10.0 10.1 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.
  11. ↑ 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.
  12. ↑ 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 1-84110-100-1.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 15.0 15.1 15.2 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ 17.0 17.1 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. PMID 11071635.
  18. ↑ 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.
  19. ↑ 19.0 19.1 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.
  20. ↑ 20.0 20.1 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.
  21. ↑ 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.
  22. ↑ 22.0 22.1 22.2 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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. PMID 1375232.
  26. ↑ 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. PMID 7680037.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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. PMID 7509796.
  33. ↑ 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. PMID 7523381.
  34. ↑ 34.0 34.1 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. PMC 121439. PMID 9528781.
  35. ↑ 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. PMC 359793. PMID 7684496.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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. PMC 359382. PMID 7526158.

Further reading

External links

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