Interleukin-3, Interleukin-5 and GM-CSF signaling (Homo sapiens)

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14, 332829, 5039, 486, 27, 29, 3022, 3521, 55589, 6710, 1644, 591224, 70181, 1534, 36, 391160, 66, 6811, 314, 373113, 4123, 42, 4649, 566119, 56, 6332, 45562821, 3821, 23125933, 4776764cytosolnucleoplasmp-Y694-STAT5A IL3:IL3RA:IL3RB:JAK2INPP5D IL3RA PIK3CA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 JAK2 PIK3R2 p-Y-SHC1 FYN-likekinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsJAK2 INPPL1 p-Y700,Y731,Y774-CBL p-Y700,Y731,Y774-CBL p-Y364,Y418,Y536-IL2RB CSF2RA p-Y-JAK1 CBL CSF2RA High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-Bc:SHC1ADPIL5 IL3RA IL5RA STAT5B SYK PIK3CA CSF2RA SOS1 PIK3R2 PIK3CB PIK3CD CRKL YES1 PIK3R2 SYK INPPL1 CSF2 CSF2RA p-Y699-STAT5B PIK3CB JAK2 p-Y699-STAT5B PIK3CB IL2 IL2 CSF2RB IL5 PTPN6 p85-containing Class1A PI3KsJAK3 PIK3CD IL5 ATPGRB2-1 CRKL p-Y364,Y418,Y536-IL2RB JAK2 RAF/MAP kinasecascadeCSF2RA JAK3 CSF2RA IL2RG GRB2-1SHIP1,2JAK2 PTPN6 IL3RA PTPN11 IL2RG IL5RA Interleukin receptorcomplexes withactivated SHC1IL5 p(Y700,731,774)-CBL:VAV1PTPN11ATPIL5 p-Y593,Y628-CSF2RB JAK2 IL5 IL2 Unkown tyrosinekinasep-Y349,Y350,Y427-SHC1 IL2RA IL3 p-Y1007-JAK2 PIK3CA PIK3R1 p-Y-SHC1 JAK3 SYK YWHAZSHC1 IL3 JAK2 JAK2 JAK3 HCK IL5RA K63polyUb-PIK3R1 GAB2 GRB2-1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 BLNK PTPN6 p-Y593-CSF2RB YES1 CSF2RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 CRK p-Y-JAK1 YES1 IL5RA GRB2-1 CSF2 IL2RG PIK3CD PTPN11 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593)-Bc:SHP1, SHP2IL3 p-Y-SHC1 FYN-likekinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsGM-CSF:GM-CSFreceptor alphasubunitFYN-like kinasesCSF2RB JAK2 IL2 VAV1BLNKVAV1 CSF2RA ATPp-Y593,Y628-CSF2RB IL2RA IL3RA GRB2-1:SOS1JAK3 LYN CSF2RA IL2RG IL5RA GRB2-1 IL5RA JAK2 IL3 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 ATPTEC IL3RA K48polyUbGRB2:GAB2IL5RA FYN-likekinases:CBL:GRB2:p85-containing Class 1A PI3KsIL3RA IL3 IL5 K63polyUb-PIK3R2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL5 IL5 Interleukin receptorcomplexes withactivatedSHC1:GRB2:SOS1RAPGEF1IL5 p-Y-SHC1 IL3RAHighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p-(Y593,628)-Bc:p(427,349,350)-SHC1IL2RA p-Y364,Y418,Y536-IL2RB JAK3 SOS1 ADPIL5 homodimerPIK3R3 p-Y699-STAT5B IL5 PIK3CB IL2RA PIK3CA ATPSHC1IL2RA PIK3R1 CSF2RBIL3 CSF2 CSF2RAPIK3R3 PTPN6 IL2 Interleukin receptorcomplexes withactivatedSHC1:SHIP:GRB2p-Y-SHC1 CSF2RA IL5 PIK3R1 GAB2 RAPGEF1 IL3 p-Y-JAK1 p-Y700,Y731,Y774-CBL IL5 PIK3CD IL2RA p-Y-SHC1 CSF2RB IL5 p-Y-SHC1 PIK3R2 B-celllinkerprotein:p(Y700,731,774)-CBLInterleukin receptorcomplexes withactivatedSHC1:SHIP1IL2 GRB2-1 p-Y-GAB2 p-Y700,Y731,Y774-CBL ADPIL5RA CBLp-Y1007-JAK2 GRB2-1 p-S585-CSF2RB High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 IL2 CSF2 p-Y364,Y418,Y536-IL2RB LYN PIK3CB High affinitybinding complexdimers of cytokinereceptors using Bc.activatedJAK2:STAT5p-Y699-STAT5B p-Y-JAK1 IL3:IL3RAJAK2 CSF2 GRB2-1 p-Y364,Y418,Y536-IL2RB IL3RA IL3RA PIK3CA IL3 GRB2-1 IL2RG p(Y700,731,774)-CBL:CRK:RAPGEF1IL5RA IL3RA IL2RA Interleukin receptorcomplexes withactivatedShc:GRB2:p-GAB2IL5RA p-S585-CSF2RB PIK3R1 GM-CSF:GM-CSFreceptor alphasubunit:Common betachain:JAK2PTPN11 p-Y700,Y731,Y774-CBL IL3 CSF2RA p-Y-JAK1 JAK2 IL3 IL5 JAK2 p-Y-JAK1 CSF2RB Tyrosine kinasesthat phosphorylatethe Common betachainFYN p-STAT5 dimerIL5 p-Y694-STAT5A HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593,628)-Bc:SHP1, SHP2IL5p-Y364,Y418,Y536-IL2RB InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3KsIL5 HCK IL3 CSF2IL3RA IL5RA PIK3CD LYN p-Y-JAK1 p-Y364,Y418,Y536-IL2RB CSF2 GRB2-1 YES1 p-Y694-STAT5A CSF2 CRK IL5RA JAK3 PIK3R3 p-Y364,Y418,Y536-IL2RB p(Y700,731,774)-CBL:CRKCSF2 STAT5B CSF2RB FYN IL3p-STAT5 dimerCSF2 p-Y1007-JAK2 PIK3CD CRK JAK2 PTPN11 YWHAZ IL3 IL3RA IL2RG PIK3CB PRKACAIL3RA CSF2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 LYN IL3RA K63polyUb-PIK3R3 CSF2 CSF2RA CSF2 IL2 JAK2PTPN6,PTPN11p-S585-CSF2RB p-Y700,Y731,Y774-CBL CSF2 p-Y-SHC1 IL3 High affinitybinding complexesof interleukinreceptors using theCommon beta chainPTPN6 p-Y694-STAT5A CSF2 IL3RA High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-BcHigh affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-BcCSF2RB JAK3 TECFYN IL3RB:JAK2IL2RG TEC:VAV1IL5RA CSF2RA IL5RA High affinitybinding complexdimers of cytokinereceptors using Bc,activatedJAK2:p-STAT5VAV1 JAK2 Interleukin receptorcompexes withactivatedShc:GRB2:GAB2CSF2 p-STAT5A, p-STAT5BCSF2 Interleukin receptorcomplexes withactivatedSHC1:SHIP1,2p-Y700,Y731,Y774-CBLSYK p-Y1007-JAK2 PIK3R2 PIK3R1 SHP2:GRB2p-Y593,Y628-CSF2RB High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zetaIL3RA ADPIL3 STAT5A IL2RG INPP5D IL5 homodimer:IL5RAIL5homodimer:IL5RA:Common beta chain:JAK2HCK p-Y-JAK1 CSF2RB High affinitybinding complexdimers of cytokinereceptors using Bc,activated JAK2HCK IL5RA CSF2RA p-Y-GAB2 IL3RA IL3 IL5RA PIK3R3 YWHAZ High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2GRB2-1 CRK, CRKLCRKL IL5RAIL2RA CSF2RB STAT5A CSF2RA p-Y593,Y628-CSF2RB ADPIL3 FYN CSF2RB PIK3R3 PIK3CA CSF2RB STAT5A,STAT5BHigh affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zeta:p85-containingClass 1A PI3KsGRB2-1 CSF2RA 2, 3, 5, 8, 17...52, 5462, 69


Description

The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.

IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).

All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).

The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).



Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. View original pathway at:Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 512988
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Ray, KP

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Bibliography

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  1. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMed Europe PMC
  2. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC
  3. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC
  4. Marengère LE, Mirtsos C, Kozieradzki I, Veillette A, Mak TW, Penninger JM.; ''Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells.''; PubMed Europe PMC
  5. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC
  6. Anderson SM, Burton EA, Koch BL.; ''Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase.''; PubMed Europe PMC
  7. Behrmann I, Janzen C, Gerhartz C, Schmitz-Van de Leur H, Hermanns H, Heesel B, Graeve L, Horn F, Tavernier J, Heinrich PC.; ''A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation.''; PubMed Europe PMC
  8. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC
  9. Andoniou CE, Thien CB, Langdon WY.; ''The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain.''; PubMed Europe PMC
  10. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T.; ''Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.''; PubMed Europe PMC
  11. Stomski FC, Dottore M, Winnall W, Guthridge MA, Woodcock J, Bagley CJ, Thomas DT, Andrews RK, Berndt MC, Lopez AF.; ''Identification of a 14-3-3 binding sequence in the common beta chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors that is serine-phosphorylated by GM-CSF.''; PubMed Europe PMC
  12. Flores-Morales A, Pircher TJ, Silvennoinen O, Gustafsson JA, Sanchez-Gomez M, Norstedt G, Haldosén LA, Wood TJ.; ''In vitro interaction between STAT 5 and JAK 2; dependence upon phosphorylation status of STAT 5 and JAK 2.''; PubMed Europe PMC
  13. 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
  14. Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, Franklin RA, Oberhaus SM, Steelman LS, McCubrey JA.; ''Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs.''; PubMed Europe PMC
  15. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC
  16. Ravichandran KS, Burakoff SJ.; ''The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation.''; PubMed Europe PMC
  17. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC
  18. Song H, Zhang J, Chiang YJ, Siraganian RP, Hodes RJ.; ''Redundancy in B cell developmental pathways: c-Cbl inactivation rescues early B cell development through a B cell linker protein-independent pathway.''; PubMed Europe PMC
  19. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW.; ''The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.''; PubMed Europe PMC
  20. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC
  21. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG.; ''New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway.''; PubMed Europe PMC
  22. Machide M, Mano H, Todokoro K.; ''Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain.''; PubMed Europe PMC
  23. Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG.; ''Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins.''; PubMed Europe PMC
  24. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMed Europe PMC
  25. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC
  26. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC
  27. Park RK, Kyono WT, Liu Y, Durden DL.; ''CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling.''; PubMed Europe PMC
  28. Bone H, Dechert U, Jirik F, Schrader JW, Welham MJ.; ''SHP1 and SHP2 protein-tyrosine phosphatases associate with betac after interleukin-3-induced receptor tyrosine phosphorylation. Identification of potential binding sites and substrates.''; PubMed Europe PMC
  29. Odai H, Sasaki K, Iwamatsu A, Hanazono Y, Tanaka T, Mitani K, Yazaki Y, Hirai H.; ''The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells.''; PubMed Europe PMC
  30. Hunter S, Koch BL, Anderson SM.; ''Phosphorylation of cbl after stimulation of Nb2 cells with prolactin and its association with phosphatidylinositol 3-kinase.''; PubMed Europe PMC
  31. Guthridge MA, Stomski FC, Barry EF, Winnall W, Woodcock JM, McClure BJ, Dottore M, Berndt MC, Lopez AF.; ''Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival.''; PubMed Europe PMC
  32. Gu H, Pratt JC, Burakoff SJ, Neel BG.; ''Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation.''; PubMed Europe PMC
  33. Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF.; ''Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors.''; PubMed Europe PMC
  34. Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS.; ''Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP.''; PubMed Europe PMC
  35. Kline JB, Moore DJ, Clevenger CV.; ''Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site.''; PubMed Europe PMC
  36. Ingham RJ, Okada H, Dang-Lawson M, Dinglasan J, van Der Geer P, Kurosaki T, Gold MR.; ''Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.''; PubMed Europe PMC
  37. Miura-Shimura Y, Duan L, Rao NL, Reddi AL, Shimura H, Rottapel R, Druker BJ, Tsygankov A, Band V, Band H.; ''Cbl-mediated ubiquitinylation and negative regulation of Vav.''; PubMed Europe PMC
  38. Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ, Ravichandran KS.; ''Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor.''; PubMed Europe PMC
  39. Odai H, Sasaki K, Iwamatsu A, Nakamoto T, Ueno H, Yamagata T, Mitani K, Yazaki Y, Hirai H.; ''Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl.''; PubMed Europe PMC
  40. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC
  41. Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN.; ''JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.''; PubMed Europe PMC
  42. Dorsch M, Hock H, Diamantstein T.; ''Tyrosine phosphorylation of Shc is induced by IL-3, IL-5 and GM-CSF.''; PubMed Europe PMC
  43. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC
  44. Devos R, Plaetinck G, Van der Heyden J, Cornelis S, Vandekerckhove J, Fiers W, Tavernier J.; ''Molecular basis of a high affinity murine interleukin-5 receptor.''; PubMed Europe PMC
  45. Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC.; ''Engagement of Gab1 and Gab2 in erythropoietin signaling.''; PubMed Europe PMC
  46. Gotoh N, Tojo A, Shibuya M.; ''A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3.''; PubMed Europe PMC
  47. Stomski FC, Woodcock JM, Zacharakis B, Bagley CJ, Sun Q, Lopez AF.; ''Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor heterodimerization and activation of all three receptors.''; PubMed Europe PMC
  48. Harmer SL, DeFranco AL.; ''The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes.''; PubMed Europe PMC
  49. Orban PC, Levings MK, Schrader JW.; ''Heterodimerization of the alpha and beta chains of the interleukin-3 (IL-3) receptor is necessary and sufficient for IL-3-induced mitogenesis.''; PubMed Europe PMC
  50. Feshchenko EA, Langdon WY, Tsygankov AY.; ''Fyn, Yes, and Syk phosphorylation sites in c-Cbl map to the same tyrosine residues that become phosphorylated in activated T cells.''; PubMed Europe PMC
  51. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC
  52. 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
  53. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC
  54. 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
  55. Brockdorff JL, Gu H, Mustelin T, Kaltoft K, Geisler C, Röpke C, Ødum N.; ''Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a.''; PubMed Europe PMC
  56. Kitamura T, Sato N, Arai K, Miyajima A.; ''Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors.''; PubMed Europe PMC
  57. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC
  58. Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ.; ''FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival.''; PubMed Europe PMC
  59. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G.; ''A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF.''; PubMed Europe PMC
  60. Sakamaki K, Miyajima I, Kitamura T, Miyajima A.; ''Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.''; PubMed Europe PMC
  61. Milburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P, Wells TN.; ''A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5.''; PubMed Europe PMC
  62. Fang D, Liu YC.; ''Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells.''; PubMed Europe PMC
  63. Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A.; ''Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor.''; PubMed Europe PMC
  64. Gearing DP, King JA, Gough NM, Nicola NA.; ''Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor.''; PubMed Europe PMC
  65. 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
  66. Sorensen P, Mui AL, Krystal G.; ''Interleukin-3 stimulates the tyrosine phosphorylation of the 140-kilodalton interleukin-3 receptor.''; PubMed Europe PMC
  67. Reedquist KA, Fukazawa T, Panchamoorthy G, Langdon WY, Shoelson SE, Druker BJ, Band H.; ''Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G.''; PubMed Europe PMC
  68. Duronio V, Clark-Lewis I, Federsppiel B, Wieler JS, Schrader JW.; ''Tyrosine phosphorylation of receptor beta subunits and common substrates in response to interleukin-3 and granulocyte-macrophage colony-stimulating factor.''; PubMed Europe PMC
  69. Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC.; ''Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.''; PubMed Europe PMC
  70. Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101318view11:20, 1 November 2018ReactomeTeamreactome version 66
100855view20:52, 31 October 2018ReactomeTeamreactome version 65
100396view19:26, 31 October 2018ReactomeTeamreactome version 64
99944view16:11, 31 October 2018ReactomeTeamreactome version 63
99500view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99148view12:41, 31 October 2018ReactomeTeamreactome version 62
93872view13:42, 16 August 2017ReactomeTeamreactome version 61
93439view11:23, 9 August 2017ReactomeTeamreactome version 61
86530view09:20, 11 July 2016ReactomeTeamreactome version 56
83413view11:10, 18 November 2015ReactomeTeamVersion54
81612view13:09, 21 August 2015ReactomeTeamVersion53
77073view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76778view12:14, 16 July 2014ReactomeTeamFixed remaining interactions
76100view10:16, 11 June 2014ReactomeTeamRe-fixing comment source
75812view11:35, 10 June 2014ReactomeTeamReactome 48 Update
75162view14:11, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74809view08:54, 30 April 2014ReactomeTeamReactome46
44874view10:01, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
42059view21:53, 4 March 2011MaintBotAutomatic update
39866view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
B-cell

linker

protein:p(Y700,731,774)-CBL
ComplexR-HSA-912760 (Reactome)
BLNK ProteinQ8WV28 (Uniprot-TrEMBL)
BLNKProteinQ8WV28 (Uniprot-TrEMBL)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CRK ProteinP46108 (Uniprot-TrEMBL)
CRK, CRKLComplexR-HSA-381945 (Reactome)
CRKL ProteinP46109 (Uniprot-TrEMBL)
CSF2 ProteinP04141 (Uniprot-TrEMBL)
CSF2ProteinP04141 (Uniprot-TrEMBL)
CSF2RA ProteinP15509 (Uniprot-TrEMBL)
CSF2RAProteinP15509 (Uniprot-TrEMBL)
CSF2RB ProteinP32927 (Uniprot-TrEMBL)
CSF2RBProteinP32927 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3KsComplexR-HSA-912623 (Reactome)
FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsComplexR-HSA-912799 (Reactome)
FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsComplexR-HSA-912647 (Reactome)
FYN-like kinasesComplexR-HSA-912625 (Reactome)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GM-CSF:GM-CSF

receptor alpha subunit:Common beta

chain:JAK2
ComplexR-HSA-913389 (Reactome)
GM-CSF:GM-CSF

receptor alpha

subunit
ComplexR-HSA-913362 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:GAB2ComplexR-HSA-912522 (Reactome)
HCK ProteinP08631 (Uniprot-TrEMBL)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,

p-(Y593,628)-Bc:p(427,349,350)-SHC1
ComplexR-HSA-913439 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593)-Bc:SHP1, SHP2
ComplexR-HSA-914049 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593,628)-Bc:SHP1, SHP2
ComplexR-HSA-914086 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, activated

JAK2:p-STAT5
ComplexR-HSA-913465 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

activated JAK2
ComplexR-HSA-913405 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing

Class 1A PI3Ks
ComplexR-HSA-914177 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3

zeta
ComplexR-HSA-914180 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, inactive JAK2,

p(S589)-Bc
ComplexR-HSA-914179 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, inactive JAK2,

p(Y593,628)-Bc:SHC1
ComplexR-HSA-913458 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, inactive JAK2,

p(Y593,628)-Bc
ComplexR-HSA-913422 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2
ComplexR-HSA-913399 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc. activated

JAK2:STAT5
ComplexR-HSA-913447 (Reactome)
High affinity

binding complexes of interleukin receptors using the

Common beta chain
ComplexR-HSA-913364 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 R-HSA-914052 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 R-HSA-926768 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks R-HSA-926776 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 R-HSA-913439 (Reactome)
IL2 ProteinP60568 (Uniprot-TrEMBL)
IL2RA ProteinP01589 (Uniprot-TrEMBL)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL3 ProteinP08700 (Uniprot-TrEMBL)
IL3:IL3RA:IL3RB:JAK2ComplexR-HSA-450064 (Reactome)
IL3:IL3RAComplexR-HSA-450048 (Reactome)
IL3ProteinP08700 (Uniprot-TrEMBL)
IL3RA ProteinP26951 (Uniprot-TrEMBL)
IL3RAProteinP26951 (Uniprot-TrEMBL)
IL3RB:JAK2ComplexR-HSA-879945 (Reactome)
IL5 homodimer:IL5RA:Common beta chain:JAK2ComplexR-HSA-913423 (Reactome)
IL5 ProteinP05113 (Uniprot-TrEMBL)
IL5 homodimer:IL5RAComplexR-HSA-450056 (Reactome)
IL5 homodimerComplexR-HSA-913383 (Reactome)
IL5ProteinP05113 (Uniprot-TrEMBL)
IL5RA ProteinQ01344 (Uniprot-TrEMBL)
IL5RAProteinQ01344 (Uniprot-TrEMBL)
INPP5D ProteinQ92835 (Uniprot-TrEMBL)
INPPL1 ProteinO15357 (Uniprot-TrEMBL)
Interleukin

receptor complexes with activated

Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks
ComplexR-HSA-912535 (Reactome)
Interleukin receptor

compexes with activated

Shc:GRB2:GAB2
ComplexR-HSA-912537 (Reactome)
Interleukin receptor

complexes with activated

SHC1:GRB2:SOS1
ComplexR-HSA-921157 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP1,2
ComplexR-HSA-913393 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP1
ComplexR-HSA-913378 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP:GRB2
ComplexR-HSA-913411 (Reactome)
Interleukin receptor

complexes with activated

Shc:GRB2:p-GAB2
ComplexR-HSA-912533 (Reactome)
Interleukin receptor

complexes with

activated SHC1
ComplexR-HSA-912534 (Reactome)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
K48polyUbR-HSA-912740 (Reactome)
K63polyUb-PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
K63polyUb-PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
K63polyUb-PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3R1 Protein