Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a protein that in humans is encoded by the KITgene. Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.
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) expresses 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 prostatestem cells. In addition, mast cells, melanocytes in the skin, and interstitial cells of Cajal in the digestive tract express CD117.
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. 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. Signalling through CD117 plays a role in cell survival, proliferation, and differentiation.
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. G-CSF indirectly activates CD117. Direct CD117 agonists are currently being developed as mobilization agents.
CD117 is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer. 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. 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 leukemia), the receptor is not inhibited by imatinib. In those cases other inhibitors such as dasatinib and nilotinib can be used.
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.
^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". Genomics39 (2): 216–26. doi:10.1006/geno.1996.4482. PMID9027509.
^Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-01.
^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. PMID16166280.
^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. ISBN1-84110-100-1.
^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. PMC1223215. PMID12444928.
^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. PMID8757502.
^ abcAnzai 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". Blood99 (12): 4413–21. doi:10.1182/blood.V99.12.4413. PMID12036870.
^ abLennartsson 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. PMID12878163.
^ abvan 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". Blood96 (10): 3406–13. PMID11071635.
^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. PMID9092574.
^ abLiang X, Wisniewski D, Strife A, Shivakrupa, 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. PMID11825908.
^ abVoisset 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. PMID20117079.
^ abcDe 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. PMC1171183. PMID10022833.
^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. PMC1220349. PMID10377264.
^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. PMID8647802.
^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. PMID1375232.
^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. PMID7680037.
^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. PMID18588518.
^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. PMID9341198.
^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. PMID7536744.
^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. PMID9038210.
^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. PMID11018522.
^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. PMID7509796.
^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. PMID7523381.
^ abKozlowski 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. PMC121439. PMID9528781.
^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. PMC359793. PMID7684496.
^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. PMC1218765. PMID9355737.
^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. PMID14707129.
^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". Oncogene18 (40): 5546–53. doi:10.1038/sj.onc.1202929. PMID10523831.
^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. PMC359382. PMID7526158.
Valent P, Ghannadan M, Hauswirth AW, et al. (2003). "Signal transduction-associated and cell activation-linked antigens expressed in human mast cells". Int. J. Hematol.75 (4): 357–62. doi:10.1007/BF02982124. PMID12041664.
Sandberg AA, Bridge JA (2002). "Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors". Cancer Genet. Cytogenet.135 (1): 1–22. doi:10.1016/S0165-4608(02)00546-0. PMID12072198.
Miettinen M, Lasota J (2006). "KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation". Appl. Immunohistochem. Mol. Morphol.13 (3): 205–20. PMID16082245.
Patnaik MM, Tefferi A, Pardanani A (2007). "Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders". Current cancer drug targets7 (5): 492–503. doi:10.2174/156800907781386614. PMID17691909.
Giebel LB, Strunk KM, Holmes SA, Spritz RA (1992). "Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene". Oncogene7 (11): 2207–17. PMID1279499.
Spritz RA, Droetto S, Fukushima Y (1992). "Deletion of the KIT and PDGFRA genes in a patient with piebaldism". Am. J. Med. Genet.44 (4): 492–5. doi:10.1002/ajmg.1320440422. PMID1279971.
Spritz RA, Giebel LB, Holmes SA (1992). "Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism". Am. J. Hum. Genet.50 (2): 261–9. PMC1682440. PMID1370874.
Duronio V, Welham MJ, Abraham S, et al. (1992). "p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein". Proc. Natl. Acad. Sci. U.S.A.89 (5): 1587–91. doi:10.1073/pnas.89.5.1587. PMC48497. PMID1371879.
André C, Martin E, Cornu F, et al. (1992). "Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III". Oncogene7 (4): 685–91. PMID1373482.
Lev S, Yarden Y, Givol D (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. PMID1375232.
Fleischman RA (1992). "Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene". J. Clin. Invest.89 (6): 1713–7. doi:10.1172/JCI115772. PMC295855. PMID1376329.
Vandenbark GR, deCastro CM, Taylor H, et al. (1992). "Cloning and structural analysis of the human c-kit gene". Oncogene7 (7): 1259–66. PMID1377810.
Alai M, Mui AL, Cutler RL, et al. (1992). "Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells". J. Biol. Chem.267 (25): 18021–5. PMID1381360.
Ashman LK, Cambareri AC, To LB, et al. (1991). "Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow". Blood78 (1): 30–7. PMID1712644.