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2o26

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Structure of a class III RTK signaling assemblyStructure of a class III RTK signaling assembly

Structural highlights

2o26 is a 8 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
Gene:Kitlg, Kitl, Mgf, Sl, Slf (LK3 transgenic mice), Kit, Sl (LK3 transgenic mice)
Activity:Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

[SCF_MOUSE] Ligand for the receptor-type protein-tyrosine kinase KIT. 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. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins. [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.

Publication Abstract from PubMed

Stem cell factor (SCF) binds to and activates the KIT receptor, a class III receptor tyrosine kinase (RTK), to stimulate diverse processes including melanogenesis, gametogenesis and hematopoeisis. Dysregulation of KIT activation is associated with many cancers. We report a 2.5 A crystal structure of the functional core of SCF bound to the extracellular ligand-binding domains of KIT. The structure reveals a 'wrapping' SCF-recognition mode by KIT, in which KIT adopts a bent conformation to facilitate each of its first three immunoglobulin (Ig)-like domains to interact with SCF. Three surface epitopes on SCF, an extended loop, the B and C helices, and the N-terminal segment, contact distinct KIT domains, with two of the epitopes undergoing large conformational changes upon receptor binding. The SCF/KIT complex reveals a unique RTK dimerization assembly, and a novel recognition mode between four-helix bundle cytokines and Ig-family receptors. It serves as a framework for understanding the activation mechanisms of class III RTKs.

Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.,Liu H, Chen X, Focia PJ, He X EMBO J. 2007 Feb 7;26(3):891-901. Epub 2007 Jan 25. PMID:17255936[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

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

2o26, resolution 2.50Å

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