8s17

Structural highlights

Disease

KIT_HUMAN Defects in KIT are a cause of piebald trait (PBT) [MIM:172800; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:606764.^{[10] [11] [12] [13] [14]} Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:273300. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.^[15] Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.^[16]

Function

KIT_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.^{[17] [18] [19] [20] [21] [22] [23] [24] [25] [26]}

References

1. ↑ Fleischman RA. Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene. J Clin Invest. 1992 Jun;89(6):1713-7. PMID:1376329 doi:http://dx.doi.org/10.1172/JCI115772
2. ↑ Spritz RA, Giebel LB, Holmes SA. 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. 1992 Feb;50(2):261-9. PMID:1370874
3. ↑ Giebel LB, Spritz RA. Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8696-9. PMID:1717985
4. ↑ Spritz RA, Holmes SA, Itin P, Kuster W. Novel mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. J Invest Dermatol. 1993 Jul;101(1):22-5. PMID:7687267
5. ↑ Riva P, Milani N, Gandolfi P, Larizza L. A 12-bp deletion (7818del12) in the c-kit protooncogene in a large Italian kindred with piebaldism. Hum Mutat. 1995;6(4):343-5. PMID:8680409 doi:10.1002/humu.1380060409
6. ↑ Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP, Tulliez M. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997 Feb;96(2):374-6. PMID:9029028
7. ↑ Spritz RA, Beighton P. Piebaldism with deafness: molecular evidence for an expanded syndrome. Am J Med Genet. 1998 Jan 6;75(1):101-3. PMID:9450866
8. ↑ Nomura K, Hatayama I, Narita T, Kaneko T, Shiraishi M. A novel KIT gene missense mutation in a Japanese family with piebaldism. J Invest Dermatol. 1998 Aug;111(2):337-8. PMID:9699740 doi:10.1046/j.1523-1747.1998.00269.x
9. ↑ Syrris P, Malik NM, Murday VA, Patton MA, Carter ND, Hughes HE, Metcalfe K. Three novel mutations of the proto-oncogene KIT cause human piebaldism. Am J Med Genet. 2000 Nov 6;95(1):79-81. PMID:11074500
10. ↑ Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP, Tulliez M. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997 Feb;96(2):374-6. PMID:9029028
11. ↑ Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Matsuda H, Kitamura Y. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet. 1998 Aug;19(4):323-4. PMID:9697690 doi:10.1038/1209
12. ↑ Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998 Jan 23;279(5350):577-80. PMID:9438854
13. ↑ Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C, Larizza L. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001 Aug 1;92(3):657-62. PMID:11505412
14. ↑ Chen LL, Sabripour M, Wu EF, Prieto VG, Fuller GN, Frazier ML. A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors. Oncogene. 2005 Jun 16;24(26):4271-80. PMID:15824741 doi:1208587
15. ↑ Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP, Tulliez M. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997 Feb;96(2):374-6. PMID:9029028
16. ↑ Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP, Tulliez M. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997 Feb;96(2):374-6. PMID:9029028
17. ↑ Blume-Jensen P, Ronnstrand L, Gout I, Waterfield MD, Heldin CH. Modulation of Kit/stem cell factor receptor-induced signaling by protein kinase C. J Biol Chem. 1994 Aug 26;269(34):21793-802. PMID:7520444
18. ↑ Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA. SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain. Mol Cell Biol. 1998 Apr;18(4):2089-99. PMID:9528781
19. ↑ Taniguchi Y, London R, Schinkmann K, Jiang S, Avraham H. The receptor protein tyrosine phosphatase, PTP-RO, is upregulated during megakaryocyte differentiation and Is associated with the c-Kit receptor. Blood. 1999 Jul 15;94(2):539-49. PMID:10397721
20. ↑ Wollberg P, Lennartsson J, Gottfridsson E, Yoshimura A, Ronnstrand L. The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit. Biochem J. 2003 Mar 15;370(Pt 3):1033-8. PMID:12444928 doi:10.1042/BJ20020716
21. ↑ Lennartsson J, Wernstedt C, Engstrom U, Hellman U, Ronnstrand L. Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk. Exp Cell Res. 2003 Aug 1;288(1):110-8. PMID:12878163
22. ↑ Voytyuk O, Lennartsson J, Mogi A, Caruana G, Courtneidge S, Ashman LK, Ronnstrand L. Src family kinases are involved in the differential signaling from two splice forms of c-Kit. J Biol Chem. 2003 Mar 14;278(11):9159-66. Epub 2003 Jan 2. PMID:12511554 doi:10.1074/jbc.M211726200
23. ↑ Sun J, Pedersen M, Bengtsson S, Ronnstrand L. Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl. Exp Cell Res. 2007 Nov 1;313(18):3935-42. Epub 2007 Sep 4. PMID:17904548 doi:10.1016/j.yexcr.2007.08.021
24. ↑ Sun J, Pedersen M, Ronnstrand L. The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction. J Biol Chem. 2009 Apr 24;284(17):11039-47. doi: 10.1074/jbc.M808058200. Epub 2009, Mar 5. PMID:19265199 doi:10.1074/jbc.M808058200
25. ↑ Kim SY, Kang JJ, Lee HH, Kang JJ, Kim B, Kim CG, Park TK, Kang H. Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816. Biochem Biophys Res Commun. 2011 Jul 1;410(2):224-8. doi:, 10.1016/j.bbrc.2011.05.111. Epub 2011 May 27. PMID:21640708 doi:10.1016/j.bbrc.2011.05.111
26. ↑ Chaix A, Lopez S, Voisset E, Gros L, Dubreuil P, De Sepulveda P. Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells. J Biol Chem. 2011 Feb 25;286(8):5956-66. doi: 10.1074/jbc.M110.182642. Epub 2010 , Dec 6. PMID:21135090 doi:10.1074/jbc.M110.182642