Signaling by SCF-KIT (Homo sapiens)

From WikiPathways

Revision as of 11:22, 1 November 2018 by ReactomeTeam (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
25, 38, 41, 74, 79...48, 761828, 42, 7215, 47, 7613, 17, 70177, 9, 10, 32, 42...56, 613, 26, 56, 6935, 841735, 75, 8437, 6818, 7353, 687618, 19, 44, 7740, 41, 74168441, 64, 67, 814, 42, 55, 74456, 36, 42, 59, 605, 50, 71, 782, 3, 21, 23, 27...43506, 42, 516, 34, 42, 49, 838, 827684cytosolnucleoplasmPI3K:p-KIT:sSCFdimer:p-KIT,PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexPTPN6YES1 p-KIT (S741,746):PKCalphap-7Y-KIT ATPPIK3R3 p-Y699-STAT5B p-Y1007-JAK2 PIK3R2 LCK p-Y1007-JAK2 p-Y629-SH2B2 YES1 LYN LCK GDPGRAP2 SOS1 ADPRAC1:GDPYES1 LYN YES1 SOCS6:p-c-Kit:sSCFdimer:p-c-Kitp(Y)-GAB2:GRB2:p-SHP2:p-KIT complexp-7Y-KIT p-APS dimer:p-KITcomplexSOS1 LCK PI(4,5)P2KITLG-1(26-190) KITLG-1(26-190) GRB10 LYN p-Y699-STAT5B STAT3 GTP FYN p-STAT dimersLYN RAF/MAP kinasecascadeLCK TEC GAB2 p-S741,S746-KIT p-Y629-SH2B2 SRC-1 LCK SRC-1 CMA1 p-Y705-STAT3 p-7Y-KIT p-JAK2:SFKs:p-KITcomplex:STATsSHP2:SFKs:p-KIT:sSCFdimer:p-KITLYN VAV1FYN PTPN6 KITLG-1(26-190) p-JAK2:SFKs:p-KITcomplex:p-STATsSrc family tyrosinekinases (SFKs)p-Y-GAB2 LYN SRC-1 YES1 p-7Y-KIT KITLG-1(26-190) PIK3R1 p-7Y-KIT KITLG-1(26-190) KITLG-1(26-190)KITLG-1(26-190) KIT YES1 ADPADPPI3K alphaLYN p-7Y-KIT p-Y-GAB2 FYN GRAP GRAP2 GRB10 LNK:p-7Y-KIT:sSCFdimer:p-7Y-KITp21 RAS:GDPPIP3 activates AKTsignalingLCK LCK p21 RAS:GTPPTPRU:KITPIK3R1 KITLG-1(192-273)GAB2:GRB2:p-SHP2:p-KIT complexSRC-1 p-7Y-KIT PIK3R2 FYN CHEK1 SOCS1PIK3R3 RAC1:GTPPIK3R3 KITLG-1(26-190) p-Y546,Y584-PTPN11 KIT GTP Adapterproteins:p-KITcomplexp-7Y-KIT SOCS6 GRB2-1p-7Y-KIT CBLGDP PIK3CA FYN p-Y546,Y584-PTPN11 FYN KITLG-1(26-190) GTPSOCS1 CHEK1 FYN PIK3R1 SRC-1 YES1 KITLG-1(26-190) KITLG-1(26-190) KITLG-1(26-190) p-JAK2:SFKs:p-KITcomplex:p-STATdimersTEC ADPSRC-1 SH2B3 KITLG-1(26-190) HRAS p-7Y-KIT KITLG-1(26-190) LYN FES KITLG-1(26-190) p-7Y-KIT LYN SRC-1 PRKCA LCK NRAS GDP SFKs:p-KIT complexPIK3CA FYN p-7Y-KIT:sSCFdimer:p-7Y-KITp-7Y-KIT LCK YES1 PTPRU p-Y546,Y584-PTPN11 KITLG-1(26-190) p-Y701-STAT1-1 p-8Y-KIT YES1 GRB2-1 SRC-1 LYN PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexFYN STAT3 LCK p-Y694-STAT5A ATPADPGRB2-1 LYN KITLG-1(26-190) SRC-1 p-Y1007-JAK2 FYN p-Y694-STAT5A p-Y705-STAT3 KITSRC-1 p-7Y-KIT YES1 STATsGRAP KIT:sSCF dimer:KITSRC-1 ADPSOCS6PIK3R2 YES1 SOS1 APS dimerp-7Y-KIT YES1 SRC-1 LCK SRC-1 ADPSFKs:p-8Y-KIT:sSCFdimer:p-8Y-KITp-Y705-STAT3 KRAS YES1 p-Y-GAB2 YES1 GRB2-1 GRB2-1:SOS1p-Y694-STAT5A KITLG-1(26-190) LYN sSCF dimerEndopeptidases forSCF processingFYN YES1 PIK3CA ATPATPPI(3,4,5)P3 LYN FER p-7Y-KIT GRB7 STAT5A KITLG-1p-7Y-KIT GRB2:p-SHP2:p-KITcomplexKIT:sSCF dimerKITLG-1(26-190) Tyrosinekinases:p-KITcomplexSRC-1 LCK PI(3,4,5)P3PTPRULCK PRKCAp-Y546,Y584-PTPN11 PI3K:p-KIT:sSCFdimer:p-KITp-Y701-STAT1-1 CBL:Grb2/p-APS:p-c-Kit complexKITLG-1(26-190) p-Y142,Y160,Y174-VAV1 SH2B3GAB2APSdimer:p-c-Kit:SFKscomplexLYN LYN p-Y629-SH2B2 GRB2-1 STAT5B FYN CBL RAC1 FES YES1 FYN KITLG-1(26-190) p-7Y-KIT JAK2SH2B2 YES1 MMP9 KITLG-1(26-190) LYN SRC-1 FER GRB2-1 LCK KIT LYN SRC-1 HRAS FYN p-7Y-KIT SRC-1 KITLG-1(26-190) STAT5A LCK p-JAK2:SFKs:p-KITcomplexp-SHP2:p-KIT complexSHP-1:p-c-KitcomplexLYN PIK3R3 FYN JAK2:SFKS:p-KITcomplexp-7Y-KIT FYN ATPSTAT5B p-Y546,Y584-PTPN11 KITLG-1(26-190) STAT1 GRB2-1 p-7Y-KIT p-7Y-KIT RAC1 STAT1 Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexYES1 ADPTyrosine kinasesp-Y699-STAT5B GRB2-1 GRB2-1 SOCS1:p-KIT complexKITLG-1(26-190) NRAS KITLG-1(26-190) LCK GRB7 GRB2-1 p-Y1007-JAK2 KITLG-1(26-190) YES1 LCK PTPN11p-7Y-KIT p-Y546,Y584-PTPN11 p-Y701-STAT1-1 LCK FYN p-7Y-KIT p-7Y-KIT LYN PIK3R1 SRC-1 ATPKITLG-1(26-190) SOS1 PIK3CA p-7Y-KIT FYN KRAS SH2B2 GTPKITLG-1(26-190) GRB2:SOS1:p-KITcomplexSRC-1 FYN GDPAdapter proteinsATPKITLG-1(26-190) PTPN11 p-7Y-KIT KITLG-1(26-190) p-VAV1:PIP3LCK JAK2 PIK3R2 291, 11, 12, 14, 20...22, 2429


Description

Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1433557
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC
  2. Caruana G, Cambareri AC, Ashman LK.; ''Isoforms of c-KIT differ in activation of signalling pathways and transformation of NIH3T3 fibroblasts.''; PubMed Europe PMC
  3. Lemmon MA, Pinchasi D, Zhou M, Lax I, Schlessinger J.; ''Kit receptor dimerization is driven by bivalent binding of stem cell factor.''; PubMed Europe PMC
  4. Miyazawa K, Hendrie PC, Mantel C, Wood K, Ashman LK, Broxmeyer HE.; ''Comparative analysis of signaling pathways between mast cell growth factor (c-kit ligand) and granulocyte-macrophage colony-stimulating factor in a human factor-dependent myeloid cell line involves phosphorylation of Raf-1, GTPase-activating protein and mitogen-activated protein kinase.''; PubMed Europe PMC
  5. Feng J, Witthuhn BA, Matsuda T, Kohlhuber F, Kerr IM, Ihle JN.; ''Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.''; PubMed Europe PMC
  6. Thömmes K, Lennartsson J, Carlberg M, Rönnstrand L.; ''Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor.''; PubMed Europe PMC
  7. Tang B, Mano H, Yi T, Ihle JN.; ''Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding.''; PubMed Europe PMC
  8. Blume-Jensen P, Wernstedt C, Heldin CH, Rönnstrand L.; ''Identification of the major phosphorylation sites for protein kinase C in kit/stem cell factor receptor in vitro and in intact cells.''; PubMed Europe PMC
  9. Jhun BH, Rivnay B, Price D, Avraham H.; ''The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit.''; PubMed Europe PMC
  10. Masuhara M, Nagao K, Nishikawa M, Sasaki M, Yoshimura A, Osawa M.; ''Molecular cloning of murine STAP-1, the stem-cell-specific adaptor protein containing PH and SH2 domains.''; PubMed Europe PMC
  11. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC
  12. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC
  13. Lennartsson J, Blume-Jensen P, Hermanson M, Pontén E, Carlberg M, Rönnstrand L.; ''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.''; PubMed Europe PMC
  14. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC
  15. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD.; ''Synthesis and function of 3-phosphorylated inositol lipids.''; PubMed Europe PMC
  16. Gueller S, Gery S, Nowak V, Liu L, Serve H, Koeffler HP.; ''Adaptor protein Lnk associates with Tyr(568) in c-Kit.''; PubMed Europe PMC
  17. Tauchi T, Feng GS, Marshall MS, Shen R, Mantel C, Pawson T, Broxmeyer HE.; ''The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells.''; PubMed Europe PMC
  18. Wollberg P, Lennartsson J, Gottfridsson E, Yoshimura A, Rönnstrand L.; ''The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit.''; PubMed Europe PMC
  19. Masson K, Heiss E, Band H, Rönnstrand L.; ''Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation.''; PubMed Europe PMC
  20. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC
  21. Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J.; ''Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor.''; PubMed Europe PMC
  22. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC
  23. Piao X, Curtis JE, Minkin S, Minden MD, Bernstein A.; ''Expression of the Kit and KitA receptor isoforms in human acute myelogenous leukemia.''; PubMed Europe PMC
  24. Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC
  25. Masson K, Rönnstrand L.; ''Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.''; PubMed Europe PMC
  26. Broudy VC, Lin NL, Bühring HJ, Komatsu N, Kavanagh TJ.; ''Analysis of c-kit receptor dimerization by fluorescence resonance energy transfer.''; PubMed Europe PMC
  27. Matous JV, Langley K, Kaushansky K.; ''Structure-function relationships of stem cell factor: an analysis based on a series of human-murine stem cell factor chimera and the mapping of a neutralizing monoclonal antibody.''; PubMed Europe PMC
  28. Yi T, Ihle JN.; ''Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand.''; PubMed Europe PMC
  29. Ross D, Joyner WL.; ''Resting distribution and stimulated translocation of protein kinase C isoforms alpha, epsilon and zeta in response to bradykinin and TNF in human endothelial cells.''; PubMed Europe PMC
  30. Blechman JM, Lev S, Brizzi MF, Leitner O, Pegoraro L, Givol D, Yarden Y.; ''Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor.''; PubMed Europe PMC
  31. Mendiaz EA, Chang DG, Boone TC, Grant JR, Wypych J, Aguero B, Egrie JC, Langley KE.; ''Epitope mapping and immunoneutralization of recombinant human stem-cell factor.''; PubMed Europe PMC
  32. Craig AW, Greer PA.; ''Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells.''; PubMed Europe PMC
  33. Lev S, Yarden Y, Givol D.; ''A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses.''; PubMed Europe PMC
  34. Feng GS, Ouyang YB, Hu DP, Shi ZQ, Gentz R, Ni J.; ''Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway.''; PubMed Europe PMC
  35. Deberry C, Mou S, Linnekin D.; ''Stat1 associates with c-kit and is activated in response to stem cell factor.''; PubMed Europe PMC
  36. 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.''; PubMed Europe PMC
  37. Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR.; ''Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.''; PubMed Europe PMC
  38. Lennartsson J, Rönnstrand L.; ''The stem cell factor receptor/c-Kit as a drug target in cancer.''; PubMed Europe PMC
  39. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC
  40. Chian R, Young S, Danilkovitch-Miagkova A, Rönnstrand L, Leonard E, Ferrao P, Ashman L, Linnekin D.; ''Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant.''; PubMed Europe PMC
  41. Rönnstrand L.; ''Signal transduction via the stem cell factor receptor/c-Kit.''; PubMed Europe PMC
  42. Roskoski R.; ''Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.''; PubMed Europe PMC
  43. 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.''; PubMed Europe PMC
  44. Rao N, Dodge I, Band H.; ''The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system.''; PubMed Europe PMC
  45. Lennartsson J, Wernstedt C, Engström U, Hellman U, Rönnstrand L.; ''Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk.''; PubMed Europe PMC
  46. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC
  47. Koyasu S.; ''The role of PI3K in immune cells.''; PubMed Europe PMC
  48. Yu M, Luo J, Yang W, Wang Y, Mizuki M, Kanakura Y, Besmer P, Neel BG, Gu H.; ''The scaffolding adapter Gab2, via Shp-2, regulates kit-evoked mast cell proliferation by activating the Rac/JNK pathway.''; PubMed Europe PMC
  49. Jahn T, Seipel P, Urschel S, Peschel C, Duyster J.; ''Role for the adaptor protein Grb10 in the activation of Akt.''; PubMed Europe PMC
  50. Weiler SR, Mou S, DeBerry CS, Keller JR, Ruscetti FW, Ferris DK, Longo DL, Linnekin D.; ''JAK2 is associated with the c-kit proto-oncogene product and is phosphorylated in response to stem cell factor.''; PubMed Europe PMC
  51. Brizzi MF, Dentelli P, Lanfrancone L, Rosso A, Pelicci PG, Pegoraro L.; ''Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation.''; PubMed Europe PMC
  52. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC
  53. Alai M, Mui AL, Cutler RL, Bustelo XR, Barbacid M, Krystal G.; ''Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells.''; PubMed Europe PMC
  54. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC
  55. Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW.; ''p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein.''; PubMed Europe PMC
  56. Philo JS, Wen J, Wypych J, Schwartz MG, Mendiaz EA, Langley KE.; ''Human stem cell factor dimer forms a complex with two molecules of the extracellular domain of its receptor, Kit.''; PubMed Europe PMC
  57. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC
  58. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC
  59. Price DJ, Rivnay B, Fu Y, Jiang S, Avraham S, Avraham H.; ''Direct association of Csk homologous kinase (CHK) with the diphosphorylated site Tyr568/570 of the activated c-KIT in megakaryocytes.''; PubMed Europe PMC
  60. Mol CD, Lim KB, Sridhar V, Zou H, Chien EY, Sang BC, Nowakowski J, Kassel DB, Cronin CN, McRee DE.; ''Structure of a c-kit product complex reveals the basis for kinase transactivation.''; PubMed Europe PMC
  61. Zhang Z, Zhang R, Joachimiak A, Schlessinger J, Kong XP.; ''Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation.''; PubMed Europe PMC
  62. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC
  63. Hafizi S, Dahlbäck B.; ''Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases.''; PubMed Europe PMC
  64. Longley BJ, Tyrrell L, Ma Y, Williams DA, Halaban R, Langley K, Lu HS, Schechter NM.; ''Chymase cleavage of stem cell factor yields a bioactive, soluble product.''; PubMed Europe PMC
  65. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC
  66. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC
  67. Kawaguchi N, Horiuchi K, Becherer JD, Toyama Y, Besmer P, Blobel CP.; ''Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19.''; PubMed Europe PMC
  68. Timokhina I, Kissel H, Stella G, Besmer P.; ''Kit signaling through PI 3-kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation.''; PubMed Europe PMC
  69. Liu H, Chen X, Focia PJ, He X.; ''Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.''; PubMed Europe PMC
  70. Nicholson PR, Empereur S, Glover HR, Dilworth SM.; ''ShcA tyrosine phosphorylation sites can replace ShcA binding in signalling by middle T-antigen.''; PubMed Europe PMC
  71. Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C.; ''Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity.''; PubMed Europe PMC
  72. 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.''; PubMed Europe PMC
  73. Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A.; ''APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl.''; PubMed Europe PMC
  74. Reber L, Da Silva CA, Frossard N.; ''Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.''; PubMed Europe PMC
  75. Ning ZQ, Li J, McGuinness M, Arceci RJ.; ''STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity.''; PubMed Europe PMC
  76. Sun J, Pedersen M, Rönnstrand L.; ''Gab2 is involved in differential phosphoinositide 3-kinase signaling by two splice forms of c-Kit.''; PubMed Europe PMC
  77. Sun J, Pedersen M, Bengtsson S, Rönnstrand L.; ''Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl.''; PubMed Europe PMC
  78. Argetsinger LS, Stuckey JA, Robertson SA, Koleva RI, Cline JM, Marto JA, Myers MG, Carter-Su C.; ''Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity.''; PubMed Europe PMC
  79. Edling CE, Hallberg B.; ''c-Kit--a hematopoietic cell essential receptor tyrosine kinase.''; PubMed Europe PMC
  80. Crosier PS, Ricciardi ST, Hall LR, Vitas MR, Clark SC, Crosier KE.; ''Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia.''; PubMed Europe PMC
  81. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S.; ''Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.''; PubMed Europe PMC
  82. Blume-Jensen P, Rönnstrand L, Gout I, Waterfield MD, Heldin CH.; ''Modulation of Kit/stem cell factor receptor-induced signaling by protein kinase C.''; PubMed Europe PMC
  83. Liu SK, McGlade CJ.; ''Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc.''; PubMed Europe PMC
  84. Brizzi MF, Dentelli P, Rosso A, Yarden Y, Pegoraro L.; ''STAT protein recruitment and activation in c-Kit deletion mutants.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
101337view11:22, 1 November 2018ReactomeTeamreactome version 66
100875view20:56, 31 October 2018ReactomeTeamreactome version 65
100416view19:30, 31 October 2018ReactomeTeamreactome version 64
99966view16:14, 31 October 2018ReactomeTeamreactome version 63
99520view14:49, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99162view12:41, 31 October 2018ReactomeTeamreactome version 62
93973view13:49, 16 August 2017ReactomeTeamreactome version 61
93574view11:27, 9 August 2017ReactomeTeamreactome version 61
87186view08:05, 19 July 2016EgonwOntology Term : 'signaling pathway' added !
86676view09:23, 11 July 2016ReactomeTeamreactome version 56
83115view10:00, 18 November 2015ReactomeTeamVersion54
81455view12:59, 21 August 2015ReactomeTeamVersion53
76929view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76634view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75964view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75667view10:57, 10 June 2014ReactomeTeamReactome 48 Update
75022view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74666view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APS

dimer:p-c-Kit:SFKs

complex
ComplexR-HSA-205257 (Reactome)
APS dimerComplexR-HSA-1433305 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Adapter

proteins:p-KIT

complex
ComplexR-HSA-1433538 (Reactome)
Adapter proteinsComplexR-HSA-1433422 (Reactome)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBL:Grb2/p-APS:p-c-Kit complexComplexR-HSA-205200 (Reactome)
CBLProteinP22681 (Uniprot-TrEMBL)
CHEK1 ProteinO14757 (Uniprot-TrEMBL)
CMA1 ProteinP23946 (Uniprot-TrEMBL)
Endopeptidases for SCF processingComplexR-HSA-1433401 (Reactome)
FER ProteinP16591 (Uniprot-TrEMBL)
FES ProteinP07332 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1433545 (Reactome)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP ProteinQ13588 (Uniprot-TrEMBL)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:SOS1:p-KIT complexComplexR-HSA-205202 (Reactome)
GRB2:p-SHP2:p-KIT complexComplexR-HSA-1433549 (Reactome)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexComplexR-HSA-1433400 (Reactome)
HRAS ProteinP01112 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2:SFKS:p-KIT complexComplexR-HSA-1433493 (Reactome)
JAK2ProteinO60674 (Uniprot-TrEMBL)
KIT ProteinP10721 (Uniprot-TrEMBL)
KIT:sSCF dimer:KITComplexR-HSA-205208 (Reactome)
KIT:sSCF dimerComplexR-HSA-205166 (Reactome)
KITLG-1(192-273)ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1(26-190) ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1(26-190)ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1ProteinP21583-1 (Uniprot-TrEMBL)
KITProteinP10721 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LNK:p-7Y-KIT:sSCF dimer:p-7Y-KITComplexR-HSA-1562562 (Reactome)
LYN ProteinP07948 (Uniprot-TrEMBL)
MMP9 ProteinP14780 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1562561 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KIT,PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-9031773 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KITComplexR-HSA-205177 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCAProteinP17252 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PTPRU ProteinQ92729 (Uniprot-TrEMBL)
PTPRU:KITComplexR-HSA-1433419 (Reactome)
PTPRUProteinQ92729 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
SFKs:p-8Y-KIT:sSCF dimer:p-8Y-KITComplexR-HSA-1472120 (Reactome)
SFKs:p-KIT complexComplexR-HSA-205271 (Reactome)
SH2B2 ProteinO14492 (Uniprot-TrEMBL)
SH2B3 ProteinQ9UQQ2 (Uniprot-TrEMBL)
SH2B3ProteinQ9UQQ2 (Uniprot-TrEMBL)
SHP-1:p-c-Kit complexComplexR-HSA-205181 (Reactome)
SHP2:SFKs:p-KIT:sSCF dimer:p-KITComplexR-HSA-205267 (Reactome)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS1:p-KIT complexComplexR-HSA-1433442 (Reactome)
SOCS1ProteinO15524 (Uniprot-TrEMBL)
SOCS6 ProteinO14544 (Uniprot-TrEMBL)
SOCS6:p-c-Kit:sSCF dimer:p-c-KitComplexR-HSA-1470001 (Reactome)
SOCS6ProteinO14544 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STATsComplexR-HSA-1433551 (Reactome)
Src family tyrosine kinases (SFKs)ComplexR-HSA-211064 (Reactome)
TEC ProteinP42680 (Uniprot-TrEMBL)
Tyrosine

kinases:p-KIT

complex
ComplexR-HSA-205201 (Reactome)
Tyrosine kinasesComplexR-HSA-1433353 (Reactome)
VAV1ProteinP15498 (Uniprot-TrEMBL)
YES1 ProteinP07947 (Uniprot-TrEMBL)
p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1562560 (Reactome)
p-7Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-7Y-KIT:sSCF dimer:p-7Y-KITComplexR-HSA-205310 (Reactome)
p-8Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-APS dimer:p-KIT complexComplexR-HSA-1433276 (Reactome)
p-JAK2:SFKs:p-KIT complex:STATsComplexR-HSA-1433527 (Reactome)
p-JAK2:SFKs:p-KIT

complex:p-STAT

dimers
ComplexR-HSA-1469999 (Reactome)
p-JAK2:SFKs:p-KIT complex:p-STATsComplexR-HSA-1470000 (Reactome)
p-JAK2:SFKs:p-KIT complexComplexR-HSA-1433552 (Reactome)
p-KIT (S741,746):PKC alphaComplexR-HSA-1433473 (Reactome)
p-S741,S746-KIT ProteinP10721 (Uniprot-TrEMBL)
p-SHP2:p-KIT complexComplexR-HSA-1433530 (Reactome)
p-STAT dimersComplexR-HSA-1566924 (Reactome)
p-VAV1:PIP3ComplexR-HSA-1433526 (Reactome)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y142,Y160,Y174-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
p-Y629-SH2B2 ProteinO14492 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
sSCF dimerComplexR-HSA-1433307 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1433418 (Reactome)
ADPArrowR-HSA-1433454 (Reactome)
ADPArrowR-HSA-1433488 (Reactome)
ADPArrowR-HSA-1433506 (Reactome)
ADPArrowR-HSA-1433508 (Reactome)
ADPArrowR-HSA-1433514 (Reactome)
ADPArrowR-HSA-1433542 (Reactome)
ADPArrowR-HSA-1470009 (Reactome)
ADPArrowR-HSA-1472121 (Reactome)
ADPArrowR-HSA-205289 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
ArrowR-HSA-205319 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
R-HSA-1433506 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
mim-catalysisR-HSA-1433506 (Reactome)
APS dimerR-HSA-205319 (Reactome)
ATPR-HSA-1433418 (Reactome)
ATPR-HSA-1433454 (Reactome)
ATPR-HSA-1433488 (Reactome)
ATPR-HSA-1433506 (Reactome)
ATPR-HSA-1433508 (Reactome)
ATPR-HSA-1433514 (Reactome)
ATPR-HSA-1433542 (Reactome)
ATPR-HSA-1470009 (Reactome)
ATPR-HSA-1472121 (Reactome)
ATPR-HSA-205289 (Reactome)
Adapter

proteins:p-KIT

complex
ArrowR-HSA-1433501 (Reactome)
Adapter proteinsR-HSA-1433501 (Reactome)
CBL:Grb2/p-APS:p-c-Kit complexArrowR-HSA-205244 (Reactome)
CBLR-HSA-205244 (Reactome)
Endopeptidases for SCF processingmim-catalysisR-HSA-1433374 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexArrowR-HSA-205234 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexR-HSA-1433454 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexmim-catalysisR-HSA-1433454 (Reactome)
GAB2R-HSA-205234 (Reactome)
GDPArrowR-HSA-1433415 (Reactome)
GDPArrowR-HSA-1433471 (Reactome)
GRB2-1:SOS1R-HSA-205286 (Reactome)
GRB2-1R-HSA-1433428 (Reactome)
GRB2:SOS1:p-KIT complexArrowR-HSA-205286 (Reactome)
GRB2:SOS1:p-KIT complexmim-catalysisR-HSA-1433471 (Reactome)
GRB2:p-SHP2:p-KIT complexArrowR-HSA-1433428 (Reactome)
GRB2:p-SHP2:p-KIT complexR-HSA-205234 (Reactome)
GTPR-HSA-1433415 (Reactome)
GTPR-HSA-1433471 (Reactome)
Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexR-HSA-205244 (Reactome)
JAK2:SFKS:p-KIT complexArrowR-HSA-1433451 (Reactome)
JAK2:SFKS:p-KIT complexR-HSA-1433418 (Reactome)
JAK2:SFKS:p-KIT complexmim-catalysisR-HSA-1433418 (Reactome)
JAK2R-HSA-1433451 (Reactome)
KIT:sSCF dimer:KITArrowR-HSA-205231 (Reactome)
KIT:sSCF dimer:KITR-HSA-205289 (Reactome)
KIT:sSCF dimer:KITmim-catalysisR-HSA-205289 (Reactome)
KIT:sSCF dimerArrowR-HSA-205321 (Reactome)
KIT:sSCF dimerR-HSA-205231 (Reactome)
KITLG-1(192-273)ArrowR-HSA-1433374 (Reactome)
KITLG-1(26-190)ArrowR-HSA-1433374 (Reactome)
KITLG-1(26-190)R-HSA-1433395 (Reactome)
KITLG-1R-HSA-1433374 (Reactome)
KITR-HSA-1433423 (Reactome)
KITR-HSA-1433508 (Reactome)
KITR-HSA-205231 (Reactome)
KITR-HSA-205321 (Reactome)
LNK:p-7Y-KIT:sSCF dimer:p-7Y-KITArrowR-HSA-1562640 (Reactome)
PI(3,4,5)P3ArrowR-HSA-1433514 (Reactome)
PI(3,4,5)P3R-HSA-1433542 (Reactome)
PI(4,5)P2R-HSA-1433514 (Reactome)
PI3K alphaR-HSA-1562641 (Reactome)
PI3K alphaR-HSA-205262 (Reactome)
PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexArrowR-HSA-1562641 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KIT,PI3K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexmim-catalysisR-HSA-1433514 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KITArrowR-HSA-205262 (Reactome)
PRKCAR-HSA-1433508 (Reactome)
PRKCAmim-catalysisR-HSA-1433508 (Reactome)
PTPN11R-HSA-205238 (Reactome)
PTPN6R-HSA-205306 (Reactome)
PTPRU:KITArrowR-HSA-1433423 (Reactome)
PTPRUR-HSA-1433423 (Reactome)
R-HSA-1433374 (Reactome) SCF exists as two alternatively spliced variants, a soluble form and a membrane-bound form differing in one exon (exon 6). Both isoforms are initially membrane bound with an extracellular domain, a transmembrane segment and an intracellular region. The longer isoform is rapidly cleaved to generate a 165 aa soluble protein knows as sSCF. The SCF transcript that lacks exon 6 encodes a glycoprotein that remains membrane-bound (mSCF). Both mSCF and sSCF are bioactive but different in their efficacy in c-kit activation.
Proteases including matrix metalloprotease-9 (Heissig et al., 2002), Chymase-1 (Longley et al., 1997) and several members of the ADAMs family (Kawaguchi et al, 2007; Amour et al, 2002; Chesneau et al, 2003; Mohan et al, 2002; Roghani et al, 1999; Zou et al, 2004) have been suggested to have a role in the processing of sSCF.
R-HSA-1433395 (Reactome) sSCF exists as noncovalently associated homodimer composed of two monomers interacting head-to-head to form an elongated, slightly bent dimer. Dimerization of sSCF is a dynamic process and it may play a regulatory role in the dimerization and activation of KIT (Zhang et al, 2000; Philo et al, 1996).
R-HSA-1433410 (Reactome) SOCS1 has been identified as a KIT binding partner from the yeast two-hybrid system (Sepulveda et al, 1999). SOCS1 expression is induced upon KIT activation. It associates with KIT via its SH2 domain. SOCS1 does not inhibit KIT kinase activity directly, instead it binds to GRB2 and VAV1, and selectively inhibits SCF-induced proliferation, while not effecting survival signal (Sepulveda et al, 1999). It has been proposed that SOCS1 may interrupt signal transduction pathways downstream of JAK2 (Sepulveda et al, 1999).
R-HSA-1433415 (Reactome) Vav1, once activated by PIP3 binding and phosphorylation by Src kinases, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP.
R-HSA-1433418 (Reactome) SCF induces rapid and transient autophosphorylation of JAK2 bound to c-KIT. JAKs bound to activated, dimerized receptors cross-phosphorylate and thereby activate each other. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity (Feng et al 1997, Argetsinger et al. 2004, 2010). Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only the critical tyrosine 1007 is represented in the reaction.
R-HSA-1433423 (Reactome) Tyrosine phosphatase PTPRO associates constitutively with c-Kit independently of SCF stimulation. PTPRO undergoes phosphorylation upon SCF stimulation. The PTPRO binding site on c-Kit and the molecular mechanism by which c-Kit signaling is regulated by PTPRO have not been determined.
R-HSA-1433428 (Reactome) GRB2 can be recruited indirectly to KIT through SHP2 (Tauchi et al. 1994). Y279, Y304, Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the SHP2 short isoform) are the potential sites of SHP2 tyrosyl phosphorylation and that Y546 is the major GRB2 binding site (Feng, et al. 1993, Araki, et al. 2003). This brings Grb2:SOS1 into proximity with the plasma membrane, where it can activate Ras.
R-HSA-1433451 (Reactome) Janus kinase 2 (JAK2) plays an important role in SCF induced proliferation (Radosevic et al. 2004). JAK2 was observed to pre-associate with KIT, with increased association after SCF stimulation of KIT (Weiler et al. 1996).
R-HSA-1433454 (Reactome) GAB2 bound to GRB2 on KIT is then phosphorylated on a number of tyrosine residues through the action of Src family kinases (SFKs).
R-HSA-1433456 (Reactome) Activation of KIT mediates the recruitment of and association with STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Rönnstrand 2004).
R-HSA-1433471 (Reactome) Once recruited to the membrane in response to c-Kit stimulation, Son of sevenless (SOS1) activates the small GTPase protein Ras. SOS1 is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. SOS1 activates Ras by binding which induces a conformational change that causes the exchange of GDP with GTP. Ras proteins are membrane-bound GTPases that regulate crucial cellular processes such as growth, proliferation and differentiation. Active Ras-GTP stimulates multiple effector proteins such as Raf-1, which induce a variety of cellular responses, including initiation of mitogen activated protein kinase (MAPK) cascade signaling.
R-HSA-1433488 (Reactome) Following association with KIT, Tauchi et al. had observed phosphorylation of SHP2 (Tauchi et al. 1994). Tyrosine residues Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the short isoform) are the major sites of SHP2 tyrosyl phosphorylation. Src family kinases (SFKs) are candidates for this phosphorylation (Araki et al. 2003). The phosphorylated tyrosine residues on SHP2 can recruit the adapter protein GRB2 (Tauchi et al. 1994), but it is unclear whether GRB2 binding to SHP2 is important for KIT mediated SHP2 signaling or whether the effect of SHP2 on the RAS/ERK pathway goes through its catalytic activity.
R-HSA-1433501 (Reactome) Adapter proteins GADS, GRAP, GRB7 and GRB10 interact with activated KIT (Liu & McGlade 1998, Feng et al. 1996, Thömmes et al. 1999, Jahn et al. 2002).
R-HSA-1433506 (Reactome) APS bound to KIT is phosphorylated by tyrosine kinases in response to SCF stimulation (Wollberg et al, 2003). The C-terminal tyrosine 629 may be the target site of phosphorylation in APS (Wakioka et al, 1999).
R-HSA-1433508 (Reactome) Protein kinase C (PKC) alpha phosphorylates and regulates the activity of several receptor tyrosine kinases including KIT. PKC alpha is involved in a negative feedback loop regulating SCF induced proliferation by phosphorylating and inhibiting the kinase activity of KIT (Blume-Jensen et al. 1994, 1995). PKC alpha phosphorylates KIT on S741 and S746 of the kinase insert (Blume-Jensen et al. 1995). This serine phosphorylation inhibits KIT kinase activity and reduces the capacity of multiple SH2 containing signaling components to associate with KIT (Linnekin 1999).
R-HSA-1433514 (Reactome) PI3 kinases catalyze the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4, 5-bisphosphate (PIP2). PIP3 b