Biology:CD117

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Generic protein structure example

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. ↑ "Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes". Genomics 39 (2): 216–26. 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". EMBO J. 6 (11): 3341–51. November 1987. PMID 2448137. 
  5. ↑ "Generation of a prostate from a single adult stem cell". Nature 456 (7223): 804–8. October 2008. doi:10.1038/nature07427. PMID 18946470. 
  6. ↑ Vallentin, B.; Barlogis, V.; Piperoglou, C.; Cypowyj, S.; Zucchini, N.; Chene, M.; Navarro, F.; Farnarier, C. et al. (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. http://cancerimmunolres.aacrjournals.org/content/3/10/1109. 
  7. ↑ "c-Kit--a hematopoietic cell essential receptor tyrosine kinase". Int. J. Biochem. Cell Biol. 39 (11): 1995–8. 2007. doi:10.1016/j.biocel.2006.12.005. PMID 17350321. 
  8. ↑ Jean-Loup Huret. "KIT". Atlas of Genetics and Cytogenetics in Oncology and Haematology. http://AtlasGeneticsOncology.org/Genes/KITID127.html. Retrieved 2008-03-01. 
  9. ↑ "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. 2005. doi:10.1158/0008-5472.CAN-05-0471. PMID 16166280. 
  10. ↑ 10.0 10.1 "Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight". Journal of Biomolecular Structure & Dynamics 32 (7): 1033–46. 2014. 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
  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. ↑ "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. March 2003. doi:10.1042/BJ20020716. PMID 12444928. 
  14. ↑ "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". Br. J. Haematol. 94 (1): 5–16. July 1996. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502. 
  15. ↑ 15.0 15.1 15.2 "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors". Blood 99 (12): 4413–21. June 2002. doi:10.1182/blood.V99.12.4413. PMID 12036870. 
  16. ↑ 16.0 16.1 "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. August 2003. doi:10.1016/S0014-4827(03)00206-4. PMID 12878163. 
  17. ↑ 17.0 17.1 "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood 96 (10): 3406–13. November 2000. PMID 11071635. 
  18. ↑ "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. April 1997. doi:10.1074/jbc.272.15.10248. PMID 9092574. 
  19. ↑ 19.0 19.1 "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. April 2002. doi:10.1074/jbc.M200277200. PMID 11825908. 
  20. ↑ 20.0 20.1 "FES kinase participates in KIT-ligand induced chemotaxis". Biochem. Biophys. Res. Commun. 393 (1): 174–8. February 2010. doi:10.1016/j.bbrc.2010.01.116. PMID 20117079. 
  21. ↑ "Role for the adaptor protein Grb10 in the activation of Akt". Mol. Cell. Biol. 22 (4): 979–91. February 2002. doi:10.1128/MCB.22.4.979-991.2002. PMID 11809791. 
  22. ↑ 22.0 22.1 22.2 "Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation". EMBO J. 18 (4): 904–15. February 1999. doi:10.1093/emboj/18.4.904. PMID 10022833. 
  23. ↑ "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. July 1999. doi:10.1042/0264-6021:3410211. PMID 10377264. 
  24. ↑ "Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway". J. Biol. Chem. 271 (21): 12129–32. May 1996. doi:10.1074/jbc.271.21.12129. PMID 8647802. 
  25. ↑ "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. May 1992. PMID 1375232. 
  26. ↑ "Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor". J. Biol. Chem. 268 (6): 4399–406. February 1993. PMID 7680037. 
  27. ↑ "Adaptor protein Lnk associates with Tyr(568) in c-Kit". Biochem. J. 415 (2): 241–5. October 2008. doi:10.1042/BJ20080102. PMID 18588518. 
  28. ↑ "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. October 1997. doi:10.1074/jbc.272.43.27450. PMID 9341198. 
  29. ↑ "The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit". J. Biol. Chem. 270 (16): 9661–6. April 1995. doi:10.1074/jbc.270.16.9661. PMID 7536744. 
  30. ↑ "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. February 1997. doi:10.1074/jbc.272.9.5915. PMID 9038210. 
  31. ↑ "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. September 2000. doi:10.1016/S0014-5793(00)02036-6. PMID 11018522. 
  32. ↑ "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. February 1994. PMID 7509796. 
  33. ↑ "The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells". J. Biol. Chem. 269 (40): 25206–11. October 1994. PMID 7523381. 
  34. ↑ 34.0 34.1 "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. April 1998. PMID 9528781. 
  35. ↑ "Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand". Mol. Cell. Biol. 13 (6): 3350–8. June 1993. PMID 7684496. 
  36. ↑ "Stat1 associates with c-kit and is activated in response to stem cell factor". Biochem. J. 327 (1): 73–80. October 1997. doi:10.1042/bj3270073. PMID 9355737. 
  37. ↑ "Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling". J. Biol. Chem. 279 (13): 12249–59. March 2004. doi:10.1074/jbc.M313381200. PMID 14707129. 
  38. ↑ "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. September 1999. doi:10.1038/sj.onc.1202929. PMID 10523831. 
  39. ↑ "Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding". Mol. Cell. Biol. 14 (12): 8432–7. December 1994. PMID 7526158. 

Further reading

External links




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