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V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

PDB rendering based on 1pkg.
Available structures
1pkg, 1t45, 1t46
Identifiers
Symbols KIT; C-Kit; CD117; SCFR
External IDs OMIM164920 MGI96677 HomoloGene187 GeneCards: KIT Gene
Orthologs
Species Human Mouse
Entrez 3815 16590
Ensembl n/a ENSMUSG00000005672
UniProt n/a Q3ULJ6
RefSeq (mRNA) NM_000222 NM_021099
RefSeq (protein) NP_000213 NP_066922
Location (UCSC) n/a Chr 5:
75.86 - 75.94 Mb
PubMed search [1] [2]

CD117, also called KIT or C-kit receptor, is a cytokine receptor expressed on the surface of hematopoietic stem cells 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.[1]

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, chronic myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene.[2]

Contents

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. 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.

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

CD117 is also a marker for mouse prostate stem cells.[3]

Ligand

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

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

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

CD117 is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer.[4] 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.[5] Mutations of CD117 have also been implicated in leukemia, a cancer of hematopoietic progenitors, and gastrointestinal stromal tumors (GISTs). The efficacy of imatinib, a CD117 inhibitor, is determined by the mutation status of CD117.

See also

Interactions

CD117 has been shown to interact with MPDZ,[6] PTPN11,[7][8] CD9,[9] PTPN6,[8][10] PLCG1,[11][12] STAT1,[13] LYN,[14][15] CD81,[9] Stem cell factor,[16][17] GRB10,[18] Suppressor of cytokine signaling 1,[19] Grb2,[19][20][21] CD63,[9] DOK1,[14] BCR gene,[22] Megakaryocyte-associated tyrosine kinase,[12][23] PIK3R1,[19][11][24] CRKL[11][25] and TEC.[11][26]

References

  1. ^ 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.  
  2. ^ "Entrez Gene: KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3815.  
  3. ^ Leong KG, Wang BE, Johnson L, Gao WQ (October 2008). "Generation of a prostate from a single adult stem cell". Nature 456: 804. doi:10.1038/nature07427. PMID 18946470.  
  4. ^ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. http://AtlasGeneticsOncology.org/Genes/KITID127.html. Retrieved 2008-03-01.  
  5. ^ 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.  
  6. ^ Mancini, A; Koch A, Stefan M, Niemann H, Tamura T (Sep. 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. (NETHERLANDS) 482 (1-2): 54–8. ISSN 0014-5793. PMID 11018522.  
  7. ^ Tauchi, T; Feng G S, Marshall M S, Shen R, Mantel C, Pawson T, Broxmeyer H E (Oct. 1994). "The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells". J. Biol. Chem. (UNITED STATES) 269 (40): 25206–11. ISSN 0021-9258. PMID 7523381.  
  8. ^ a b Kozlowski, M; Larose L, Lee F, Le D M, Rottapel R, Siminovitch K A (Apr. 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. (UNITED STATES) 18 (4): 2089–99. ISSN 0270-7306. PMID 9528781.  
  9. ^ a b c Anzai, Naoyuki; Lee Younghee, Youn Byung-S, Fukuda Seiji, Kim Young-June, Mantel Charlie, Akashi Makoto, Broxmeyer Hal E (Jun. 2002). "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors". Blood (United States) 99 (12): 4413–21. ISSN 0006-4971. PMID 12036870.  
  10. ^ Yi, T; Ihle J N (Jun. 1993). "Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand". Mol. Cell. Biol. (UNITED STATES) 13 (6): 3350–8. ISSN 0270-7306. PMID 7684496.  
  11. ^ a b c d van Dijk, T B; van Den Akker E, Amelsvoort M P, Mano H, Löwenberg B, von Lindern M (Nov. 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood (UNITED STATES) 96 (10): 3406–13. ISSN 0006-4971. PMID 11071635.  
  12. ^ a b Jhun, B H; Rivnay B, Price D, Avraham H (Apr. 1995). "The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit". J. Biol. Chem. (UNITED STATES) 270 (16): 9661–6. ISSN 0021-9258. PMID 7536744.  
  13. ^ Deberry, C; Mou S, Linnekin D (Oct. 1997). "Stat1 associates with c-kit and is activated in response to stem cell factor". Biochem. J. (ENGLAND) 327 ( Pt 1): 73–80. ISSN 0264-6021. PMID 9355737.  
  14. ^ a b Liang, Xiquan; Wisniewski David, Strife Annabel, Shivakrupa , Clarkson Bayard, Resh Marilyn D (Apr. 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. (United States) 277 (16): 13732–8. doi:10.1074/jbc.M200277200. ISSN 0021-9258. PMID 11825908.  
  15. ^ Linnekin, D; DeBerry C S, Mou S (Oct. 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. (UNITED STATES) 272 (43): 27450–5. ISSN 0021-9258. PMID 9341198.  
  16. ^ 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. (UNITED STATES) 267 (15): 10866–73. ISSN 0021-9258. PMID 1375232.  
  17. ^ Blechman, J M; Lev S, Brizzi M F, Leitner O, Pegoraro L, Givol D, Yarden Y (Feb. 1993). "Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor". J. Biol. Chem. (UNITED STATES) 268 (6): 4399–406. ISSN 0021-9258. PMID 7680037.  
  18. ^ Jahn, Thomas; Seipel Petra, Urschel Susanne, Peschel Christian, Duyster Justus (Feb. 2002). "Role for the adaptor protein Grb10 in the activation of Akt". Mol. Cell. Biol. (United States) 22 (4): 979–91. ISSN 0270-7306. PMID 11809791.  
  19. ^ a b c De Sepulveda, P; Okkenhaug K, Rose J L, Hawley R G, Dubreuil P, Rottapel R (Feb. 1999). "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". EMBO J. (ENGLAND) 18 (4): 904–15. doi:10.1093/emboj/18.4.904. ISSN 0261-4189. PMID 10022833.  
  20. ^ Thömmes, K; Lennartsson J, Carlberg M, Rönnstrand L (Jul. 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. (ENGLAND) 341 ( Pt 1): 211–6. ISSN 0264-6021. PMID 10377264.  
  21. ^ Feng, G S; Ouyang Y B, Hu D P, Shi Z Q, 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. (UNITED STATES) 271 (21): 12129–32. ISSN 0021-9258. PMID 8647802.  
  22. ^ Hallek, M; Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb H J, Druker B, Griffin J D, Emmerich B, Ullrich A (Jul. 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". Br. J. Haematol. (ENGLAND) 94 (1): 5–16. ISSN 0007-1048. PMID 8757502.  
  23. ^ Price, D J; Rivnay B, Fu Y, Jiang S, Avraham S, Avraham H (Feb. 1997). "Direct association of Csk homologous kinase (CHK) with the diphosphorylated site Tyr568/570 of the activated c-KIT in megakaryocytes". J. Biol. Chem. (UNITED STATES) 272 (9): 5915–20. ISSN 0021-9258. PMID 9038210.  
  24. ^ Serve, H; Hsu Y C, Besmer P (Feb. 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. (UNITED STATES) 269 (8): 6026–30. ISSN 0021-9258. PMID 7509796.  
  25. ^ Sattler, M; Salgia R, Shrikhande G, Verma S, Pisick E, Prasad K V, Griffin J D (Apr. 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. (UNITED STATES) 272 (15): 10248–53. ISSN 0021-9258. PMID 9092574.  
  26. ^ Tang, B; Mano H, Yi T, Ihle J N (Dec. 1994). "Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding". Mol. Cell. Biol. (UNITED STATES) 14 (12): 8432–7. ISSN 0270-7306. PMID 7526158.  

Further reading

  • Linnekin D (2000). "Early signaling pathways activated by c-Kit in hematopoietic cells.". Int. J. Biochem. Cell Biol. 31 (10): 1053–74. doi:10.1016/S1357-2725(99)00078-3. PMID 10582339.  
  • Canonico B, Felici C, Papa S (2001). "CD117.". J. Biol. Regul. Homeost. Agents 15 (1): 90–4. PMID 11388751.  
  • Gupta R, Bain BJ, Knight CL (2002). "Cytogenetic and molecular genetic abnormalities in systemic mastocytosis.". Acta Haematol. 107 (2): 123–8. doi:10.1159/000046642. PMID 11919394.  
  • 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. PMID 12041664.  
  • 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. PMID 12072198.  
  • Kitamura Y, Hirotab S (2005). "Kit as a human oncogenic tyrosine kinase.". Cell. Mol. Life Sci. 61 (23): 2924–31. doi:10.1007/s00018-004-4273-y. PMID 15583854.  
  • Larizza L, Magnani I, Beghini A (2005). "The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia.". Leuk. Lymphoma 46 (2): 247–55. doi:10.1080/10428190400007565. PMID 15621809.  
  • 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. PMID 16082245.  
  • Lasota J, Miettinen M (2007). "KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs).". Semin Diagn Pathol 23 (2): 91–102. doi:10.1053/j.semdp.2006.08.006. PMID 17193822.  
  • 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 targets 7 (5): 492–503. doi:10.2174/156800907781386614. PMID 17691909.  
  • 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.". Oncogene 7 (11): 2207–17. PMID 1279499.  
  • 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. PMID 1279971.  
  • 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. PMID 1370874.  
  • 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. PMID 1371879.  
  • 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.". Oncogene 7 (4): 685–91. PMID 1373482.  
  • 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. PMID 1375232.  
  • 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. PMID 1376329.  
  • Vandenbark GR, deCastro CM, Taylor H, et al. (1992). "Cloning and structural analysis of the human c-kit gene.". Oncogene 7 (7): 1259–66. PMID 1377810.  
  • 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. PMID 1381360.  
  • 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.". Blood 78 (1): 30–7. PMID 1712644.  

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