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

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5, 295046, 6130, 635, 95042234, 6918, 4312, 16565548, 553, 25, 594936, 51, 554426, 333720, 4240, 631053, 663447, 7117, 31, 33, 5723, 626, 4922, 27, 396541, 354422, 637, 2118, 45, 70nucleoplasmcytosolPIK3R1 IL3 CRK p-Y364,Y418,Y536-IL2RB CSF2 HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593,628)-Bc:SHP1, SHP2TEC YWHAZPIK3R3 FYN-likekinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsPIK3CA IL5RA IL2RG JAK2 p-Y-JAK1 p-Y700,Y731,Y774-CBL PIK3CD CSF2RA JAK3 SYK p-Y-JAK1 PIK3CD IL2RG IL5 FYN Interleukin receptorcomplexes withactivatedSHC1:SHIP1IL5RA PTPN11 p-Y593,Y628-CSF2RB CSF2RA STAT5B High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zeta:p85-containingClass 1A PI3KsPIK3CA CSF2RB GRB2:GAB2IL5 CSF2 p-Y699-STAT5B IL5RA p-Y-JAK1 IL3RA GRB2-1 PIK3R1 IL3 IL3RA IL3 IL3RA p-Y-SHC1 IL2 p-STAT5 dimerp-Y-JAK1 JAK3 p-Y1007-JAK2 CSF2RA IL2 p-S585-CSF2RB IL5 IL3RB:JAK2p-Y699-STAT5B STAT5A GAB2 CSF2RB CSF2 CSF2RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL3 CSF2RA FYN p-Y593-CSF2RB CSF2 High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zetaIL5 homodimer:IL5RAIL2 IL5 CSF2RBLYN IL5IL5RA IL2 PIK3R1 PIK3CB High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-BcRAPGEF1 IL5RAIL5 IL3 IL3 p-STAT5 dimerIL2RA PTPN6 PIK3CB BLNKGRB2-1 FYN-likekinases:CBL:GRB2:p85-containing Class 1A PI3KsIL5RA SYK 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 VAV1 InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3KsHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 CSF2RA JAK2 IL3RA K63polyUb-PIK3R1 CSF2 IL3RA JAK2 JAK3 ADPInterleukin receptorcomplexes withactivatedShc:GRB2:p-GAB2IL2RG INPPL1 JAK2 SHP2:GRB2High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2IL2RA p-Y-JAK1 p-Y-SHC1 IL5RA p-Y364,Y418,Y536-IL2RB FYN CRKL IL3RA PIK3CD TEC:VAV1IL2RG SHC1YES1 p-Y364,Y418,Y536-IL2RB p-S585-CSF2RB p-Y364,Y418,Y536-IL2RB IL3RA High affinitybinding complexesof interleukinreceptors using theCommon beta chainp-Y700,Y731,Y774-CBL CSF2RA PIK3CD ATPCSF2RB PIK3CB CSF2 IL2RA Interleukin receptorcomplexes withactivated SHC1CSF2 LYN IL3RA PTPN6 RAPGEF1p-Y1007-JAK2 p(Y700,731,774)-CBL:CRKYES1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL2RG IL3:IL3RALYN IL5 CSF2RB PIK3CA STAT5A PTPN6 p-Y593,Y628-CSF2RB PRKACAJAK3 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 ATPHCK PTPN11 PIK3R1 GRB2-1 GM-CSF:GM-CSFreceptor alphasubunit:Common betachain:JAK2GRB2-1 PIK3CB ADPIL5 YWHAZ High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 p-Y700,Y731,Y774-CBL CSF2RA p-Y364,Y418,Y536-IL2RB PIK3CB High affinitybinding complexdimers of cytokinereceptors using Bc,activatedJAK2:p-STAT5FYN-like kinasesInterleukin receptorcomplexes withactivatedSHC1:SHIP:GRB2High affinitybinding complexdimers of cytokinereceptors using Bc,activated JAK2IL5 p-Y-JAK1 p-Y700,Y731,Y774-CBL PTPN6 Unkown tyrosinekinaseHCK IL3RA IL2RA p-Y364,Y418,Y536-IL2RB GRB2-1 CSF2RA CBL PIK3R2 p-Y349,Y350,Y427-SHC1 IL3RA PIK3CA Interleukin receptorcompexes withactivatedShc:GRB2:GAB2CSF2RA CSF2 High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-Bc:SHC1FYN GAB2 IL5 CSF2 ADPIL5 CSF2 IL2 p-Y-SHC1 IL5 CSF2 p-Y699-STAT5B PIK3CB Tyrosine kinasesthat phosphorylatethe Common betachainp(Y700,731,774)-CBL:CRK:RAPGEF1IL5RA GRB2-1High affinitybinding complexdimers of cytokinereceptors using Bc.activatedJAK2:STAT5IL2RA IL3RA PTPN11 p-Y694-STAT5A IL5RA GRB2-1 JAK2 PIK3R1 CSF2 PTPN11 IL2RA CSF2RA CSF2RAINPPL1 GRB2-1 PTPN11PTPN6 IL5 CRKL IL3 PIK3R3 CRK IL3 IL3 K48polyUbCSF2RA JAK2 p(Y700,731,774)-CBL:VAV1HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p-(Y593,628)-Bc:p(427,349,350)-SHC1PIK3R3 p-Y364,Y418,Y536-IL2RB IL2RA CSF2 GRB2-1 CSF2RB p-Y-SHC1 p-Y-GAB2 RAF/MAP kinasecascadep-Y-SHC1 p-Y-SHC1 JAK2 GRB2-1:SOS1IL3JAK2 STAT5A,STAT5BCSF2RA IL5 JAK2 JAK3 VAV1SHIP1,2IL3 PIK3R2 CRK ADPp-Y-JAK1 Interleukin receptorcomplexes withactivatedSHC1:GRB2:SOS1IL5RA IL3RA p-Y700,Y731,Y774-CBL GRB2-1 STAT5B IL5RA K63polyUb-PIK3R3 PIK3R2 IL5 homodimerHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 CSF2 IL5RA YES1 IL2 High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-BcCSF2RB ADPYES1 IL2RG HCK p-Y694-STAT5A IL3 CRKL JAK2LYN p-STAT5A, p-STAT5BCSF2RA CBLJAK3 ATPSOS1 IL3 p-Y1007-JAK2 p-Y700,Y731,Y774-CBLCSF2RB PIK3CA B-celllinkerprotein:p(Y700,731,774)-CBLHCK IL5RA IL3 INPP5D p-Y-JAK1 IL3:IL3RA:IL3RB:JAK2IL3RAPIK3R2 JAK2 PIK3R2 IL3 CSF2 PIK3R3 IL3RA p-Y694-STAT5A p-Y694-STAT5A VAV1 Interleukin receptorcomplexes withactivatedSHC1:SHIP1,2p-Y-SHC1 JAK2 IL3RA FYN-likekinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ksp-Y700,Y731,Y774-CBL IL5 CSF2 JAK3 CRK, CRKLIL2RG CSF2RB p-S585-CSF2RB JAK2 PIK3CD IL5homodimer:IL5RA:Common beta chain:JAK2p-Y1007-JAK2 CSF2RB IL2 p-Y593,Y628-CSF2RB IL5RA PIK3CA PIK3R3 SHC1 SOS1 PTPN6,PTPN11HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593)-Bc:SHP1, SHP2BLNK SYK JAK2 TECIL3 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL2 IL5 GM-CSF:GM-CSFreceptor alphasubunitGRB2-1 PIK3CD GRB2-1 IL5RA JAK3 IL3RA IL2RA IL5 IL5RA p-Y699-STAT5B K63polyUb-PIK3R2 CSF2RA SYK JAK2 IL2RG p-Y-GAB2 ATPp-Y364,Y418,Y536-IL2RB INPP5D CSF2RA IL3RA YWHAZ IL5 JAK2 p-Y-SHC1 ATPp-Y593,Y628-CSF2RB p85-containing Class1A PI3KsCSF2CSF2RB IL3 IL5RA 38, 41142, 8, 11, 15, 19...13, 64


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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Pathway is converted from Reactome ID: 512988
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Reactome version: 75
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Reactome Author: Ray, KP

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114742view16:22, 25 January 2021ReactomeTeamReactome version 75
113186view11:25, 2 November 2020ReactomeTeamReactome version 74
112414view15:35, 9 October 2020ReactomeTeamReactome version 73
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:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (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)