2o26

Structural highlights

Disease

KIT_MOUSE Note=Defects in Kit are the cause of the white-spotting phenotype (W). White-spotting variants induces severe effects on pigmentation, gametogenesis and hematopoiesis. Mice homozygous for W42 die perinatally of macrocytic anemia.^{[1] [2] [3] [4] [5] [6] [7] [8]}

Function

KIT_MOUSE 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.^{[9] [10] [11] [12] [13] [14] [15]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Tyrosine kinase 3D structures

References

1. ↑ Reith AD, Ellis C, Lyman SD, Anderson DM, Williams DE, Bernstein A, Pawson T. Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase. EMBO J. 1991 Sep;10(9):2451-9. PMID:1714377
2. ↑ Serve H, Hsu YC, Besmer P. 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. 1994 Feb 25;269(8):6026-30. PMID:7509796
3. ↑ 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
4. ↑ Yee NS, Hsiau CW, Serve H, Vosseller K, Besmer P. Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C. J Biol Chem. 1994 Dec 16;269(50):31991-8. PMID:7527401
5. ↑ Voisset E, Lopez S, Dubreuil P, De Sepulveda P. The tyrosine kinase FES is an essential effector of KITD816V proliferation signal. Blood. 2007 Oct 1;110(7):2593-9. Epub 2007 Jun 26. PMID:17595334 doi:10.1182/blood-2007-02-076471
6. ↑ Liu H, Chen X, Focia PJ, He X. Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases. EMBO J. 2007 Feb 7;26(3):891-901. Epub 2007 Jan 25. PMID:17255936
7. ↑ Tan JC, Nocka K, Ray P, Traktman P, Besmer P. The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase. Science. 1990 Jan 12;247(4939):209-12. PMID:1688471
8. ↑ Nocka K, Tan JC, Chiu E, Chu TY, Ray P, Traktman P, Besmer P. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J. 1990 Jun;9(6):1805-13. PMID:1693331
9. ↑ Nocka K, Buck J, Levi E, Besmer P. Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors. EMBO J. 1990 Oct;9(10):3287-94. PMID:1698611
10. ↑ Reith AD, Ellis C, Lyman SD, Anderson DM, Williams DE, Bernstein A, Pawson T. Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase. EMBO J. 1991 Sep;10(9):2451-9. PMID:1714377
11. ↑ Serve H, Hsu YC, Besmer P. 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. 1994 Feb 25;269(8):6026-30. PMID:7509796
12. ↑ Sette C, Bevilacqua A, Geremia R, Rossi P. Involvement of phospholipase Cgamma1 in mouse egg activation induced by a truncated form of the C-kit tyrosine kinase present in spermatozoa. J Cell Biol. 1998 Aug 24;142(4):1063-74. PMID:9722617
13. ↑ 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
14. ↑ Samayawardhena LA, Pallen CJ. Protein-tyrosine phosphatase alpha regulates stem cell factor-dependent c-Kit activation and migration of mast cells. J Biol Chem. 2008 Oct 24;283(43):29175-85. doi: 10.1074/jbc.M804077200. Epub 2008, Aug 25. PMID:18725415 doi:10.1074/jbc.M804077200
15. ↑ Chen S, Burgin S, McDaniel A, Li X, Yuan J, Chen M, Khalaf W, Clapp DW, Yang FC. Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase. Am J Pathol. 2010 Dec;177(6):3125-32. doi: 10.2353/ajpath.2010.100369. Epub 2010 , Oct 29. PMID:21037083 doi:10.2353/ajpath.2010.100369
16. ↑ Liu H, Chen X, Focia PJ, He X. Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases. EMBO J. 2007 Feb 7;26(3):891-901. Epub 2007 Jan 25. PMID:17255936