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

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1, 3648, 63, 648, 2414589, 1819, 2525, 3135, 4220, 28, 5739, 6611, 30, 44654541, 6221, 32, 5526911, 546023, 3810, 50, 5221, 6118586, 27, 34, 4225, 636646, 473, 362145, 3313, 29533345cytosolnucleoplasmHigh affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2JAK2 CSF2RB p-Y593,Y628-CSF2RB High affinitybinding complexdimers of cytokinereceptors using Bc,activatedJAK2:p-STAT5PTPN11 IL3RA CSF2RA CSF2RB p-Y593,Y628-CSF2RB CBLIL3 p-S585-CSF2RB p-Y349,Y350,Y427-SHC1 GRB2-1IL5 IL5 IL5RA p-Y700,Y731,Y774-CBLIL5RA IL5RA p-Y349,Y350,Y427-SHC1 IL3RA PIK3CD High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-BcATPFYN-likekinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsIL3 TEC CSF2RA GRB2-1 IL2RA IL2 Interleukin receptorcomplexes withactivatedSHC1:GRB2:SOS1CRKL JAK3 IL3:IL3RAB-celllinkerprotein:p(Y700,731,774)-CBLHighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p-(Y593,628)-Bc:p(427,349,350)-SHC1IL2 CSF2 p(Y700,731,774)-CBL:CRKIL2RA PIK3CA Interleukin receptorcomplexes withactivatedSHC1:SHIP1,2CRK High affinitybinding complexdimers of cytokinereceptors using Bc.activatedJAK2:STAT5CSF2 FYN-likekinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsGAB2 YWHAZ IL5homodimer:IL5RA:Common beta chain:JAK2p-Y-SHC1 CSF2RBPIK3CB GM-CSF:GM-CSFreceptor alphasubunitGRB2-1 CSF2RA High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zetaJAK2 IL3RB:JAK2SHIP1,2JAK2 IL5RA IL2RA p-STAT5 dimerCSF2 SOS1 JAK2 IL3RAIL3RA IL5RA TECPIK3CB CSF2 p-Y700,Y731,Y774-CBLp-Y-SHC1 PTPN6,PTPN11CSF2RA TEC:VAV1ADPRAPGEF1IL5 BLNKGRB2-1 p-Y349,Y350,Y427-SHC1 GRB2-1:SOS1FYN-likekinases:CBL:GRB2:p85-containing Class 1A PI3KsGRB2:GAB2IL5 IL3RA p-Y700,Y731,Y774-CBLPTPN11 IL3:IL3RA:IL3RB:JAK2GRB2-1 High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-BcPIK3CB CSF2RAADPp-Y700,Y731,Y774-CBLp-Y593,Y628-CSF2RB PIK3CA p-Y364,Y418,Y536-IL2RB p-Y593,Y628-CSF2RB CSF2 IL5 IL3RA IL2 ATPATPVAV1 IL3 CRKL PTPN6 STAT5IL5RAIL5RA ATPPIK3CA p-Y-SHC1 p-Y-JAK1 PRKACAIL2RG High affinitybinding complexdimers of cytokinereceptors using Bc,activated JAK2IL3 ADPCSF2RA VAV1 InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3KsJAK2 Interleukin receptorcompexes withactivatedShc:GRB2:GAB2CSF2p-Y-JAK1 p-STAT5 dimerGRB2-1 IL3GM-CSF:GM-CSFreceptor alphasubunit:Common betachain:JAK2High affinitybinding complexesof interleukinreceptors using theCommon beta chainCSF2RA K48polyUbJAK2 p85-containing Class1A PI3KsTyrosine kinasesthat phosphorylatethe Common betachainINPPL1 RAPGEF1 IL2RG PTPN11CSF2RA p-Y364,Y418,Y536-IL2RB ADPGRB2-1 p(Y700,731,774)-CBL:VAV1JAK2JAK3 PIK3CB IL5GRB2-1 p-Y-JAK1 p-Y593,Y628-CSF2RB IL3 CSF2RB BLNK IL3 IL5 IL2RG IL5RA IL5RA GRB2-1 IL5RA CSF2 CRK IL5 homodimerJAK2 p-Y700,Y731,Y774-CBLIL3RA IL5 p-Y-JAK1 p-Y364,Y418,Y536-IL2RB IL3 Interleukin receptorcomplexes withactivatedShc:GRB2:p-GAB2HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593,628)-Bc:SHP1, SHP2p-Y-SHC1 PTPN6 CSF2 CSF2RB IL3RA IL3 CSF2RA PIK3CD FYN-like kinasesPIK3CD SHC1JAK2 PTPN6 YWHAZ Interleukin receptorcomplexes withactivatedSHC1:SHIP1RAF/MAP kinasecascadePIK3CA p(Y700,731,774)-CBL:CRK:RAPGEF1IL3 High affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(S589)-Bc:14-3-3zeta:p85-containingClass 1A PI3KsCRK, CRKLHigh affinitybinding complexdimers of cytokinereceptors using Bc,inactive JAK2,p(Y593,628)-Bc:SHC1VAV1IL3 HighaffinitybindingcomplexdimersofcytokinereceptorsusingBc,inactiveJAK2,p(Y593)-Bc:SHP1, SHP2INPP5D IL5RA p-Y349,Y350,Y427-SHC1 JAK3 ATPp-Y593-CSF2RB CBL CSF2 Interleukin receptorcomplexes withactivatedSHC1:SHIP:GRB2p-Y700,Y731,Y774-CBLYWHAZIL5 IL5 IL2 SOS1 CSF2 IL2RG IL3RA SHP2:GRB2IL2RA JAK2 IL5 CSF2RA CSF2RA PTPN11 IL5 homodimer:IL5RAADPPIK3CD CSF2 JAK2 JAK2 Interleukin receptorcomplexes withactivated SHC1p-Y364,Y418,Y536-IL2RB PTPN6 IL3RA IL5 JAK2 p-Y700,Y731,Y774-CBLJAK3 p-STAT5A/Bp-S585-CSF2RB IL3RA 2, 7, 12, 15-17, 22...


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. Source:Reactome.

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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

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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, CRKLR-HSA-912777 (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-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 kinasesR-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)
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)
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		R-HSA-913465 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

activated JAK2		R-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		R-HSA-914179 (Reactome)
High affinity

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

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

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

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

binding complex dimers of cytokine receptors using Bc,

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

binding complex dimers of cytokine receptors using Bc. activated

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

binding complexes of interleukin receptors using the

Common beta chain		R-HSA-913364 (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		R-HSA-912535 (Reactome)
Interleukin receptor

compexes with activated

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

complexes with

activated SHC1		R-HSA-912534 (Reactome)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
K48polyUbR-HSA-912740 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PRKACAProteinP17612 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6,PTPN11R-HSA-389744 (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).
RAPGEF1 ProteinQ13905 (Uniprot-TrEMBL)
RAPGEF1ProteinQ13905 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SHIP1,2R-HSA-913467 (Reactome)
SHP2:GRB2ComplexR-HSA-914028 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STAT5R-HSA-452094 (Reactome)
TEC ProteinP42680 (Uniprot-TrEMBL)
TEC:VAV1ComplexR-HSA-912729 (Reactome)
TECProteinP42680 (Uniprot-TrEMBL)
Tyrosine kinases

that phosphorylate the Common beta

chain		R-HSA-904816 (Reactome)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1ProteinP15498 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
YWHAZProteinP63104 (Uniprot-TrEMBL)
p(Y700,731,774)-CBL:CRK:RAPGEF1ComplexR-HSA-914209 (Reactome)
p(Y700,731,774)-CBL:CRKComplexR-HSA-912774 (Reactome)
p(Y700,731,774)-CBL:VAV1ComplexR-HSA-912755 (Reactome)
p-S585-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-STAT5 dimerR-HSA-507919 (Reactome)
p-STAT5 dimerR-HSA-508012 (Reactome)
p-STAT5A/BR-HSA-507929 (Reactome)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y349,Y350,Y427-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y364,Y418,Y536-IL2RB ProteinP14784 (Uniprot-TrEMBL)
p-Y593,Y628-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-Y593-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-Y700,Y731,Y774-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y700,Y731,Y774-CBLProteinP22681 (Uniprot-TrEMBL)
p85-containing Class 1A PI3KsR-HSA-508248 (Reactome) This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used experimentally (especially where p85-Abs are used) - the other forms are rarely shown experimentally. Also note it may not be the most relevant physiologically in some cell types (e.g. T cells).

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-879907 (Reactome)
ADPArrowR-HSA-879909 (Reactome)
ADPArrowR-HSA-879910 (Reactome)
ADPArrowR-HSA-912527 (Reactome)
ADPArrowR-HSA-912629 (Reactome)
ATPR-HSA-879907 (Reactome)
ATPR-HSA-879909 (Reactome)
ATPR-HSA-879910 (Reactome)
ATPR-HSA-912527 (Reactome)
ATPR-HSA-912629 (Reactome)
B-cell

linker

protein:p(Y700,731,774)-CBL		ArrowR-HSA-912724 (Reactome)
BLNKR-HSA-912724 (Reactome)
CBLR-HSA-879917 (Reactome)
CRK, CRKLR-HSA-912790 (Reactome)
CSF2R-HSA-913360 (Reactome)
CSF2RAR-HSA-913360 (Reactome)
CSF2RBR-HSA-879937 (Reactome)
FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3KsArrowR-HSA-879917 (Reactome)
FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3KsR-HSA-912629 (Reactome)
FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3Ksmim-catalysisR-HSA-912629 (Reactome)
FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsArrowR-HSA-912627 (Reactome)
FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsArrowR-HSA-912629 (Reactome)
FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsR-HSA-912627 (Reactome)
FYN-like kinasesR-HSA-879917 (Reactome)
GM-CSF:GM-CSF

receptor alpha subunit:Common beta

chain:JAK2		ArrowR-HSA-913371 (Reactome)
GM-CSF:GM-CSF

receptor alpha

subunit		ArrowR-HSA-913360 (Reactome)
GM-CSF:GM-CSF

receptor alpha

subunit		R-HSA-913371 (Reactome)
GRB2-1:SOS1R-HSA-453111 (Reactome)
GRB2-1R-HSA-879917 (Reactome)
GRB2-1R-HSA-913424 (Reactome)
GRB2-1R-HSA-914022 (Reactome)
GRB2:GAB2R-HSA-453104 (Reactome)
High

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

p-(Y593,628)-Bc:p(427,349,350)-SHC1		ArrowR-HSA-879925 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593)-Bc:SHP1, SHP2		ArrowR-HSA-914036 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593,628)-Bc:SHP1, SHP2		ArrowR-HSA-909738 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593,628)-Bc:SHP1, SHP2		R-HSA-914036 (Reactome)
High

affinity binding complex dimers of cytokine receptors using Bc, inactive

JAK2,p(Y593,628)-Bc:SHP1, SHP2		mim-catalysisR-HSA-914036 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, activated

JAK2:p-STAT5		ArrowR-HSA-879909 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc, activated

JAK2:p-STAT5		R-HSA-921155 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

activated JAK2		ArrowR-HSA-879910 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

activated JAK2		ArrowR-HSA-921155 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

activated JAK2		R-HSA-879930 (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		ArrowR-HSA-914182 (Reactome)
High affinity

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

zeta		ArrowR-HSA-912757 (Reactome)
High affinity

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

zeta		R-HSA-914182 (Reactome)
High affinity

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

p(S589)-Bc		ArrowR-HSA-913451 (Reactome)
High affinity

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

p(S589)-Bc		R-HSA-912757 (Reactome)
High affinity

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

p(Y593,628)-Bc:SHC1		ArrowR-HSA-879934 (Reactome)
High affinity

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

p(Y593,628)-Bc:SHC1		R-HSA-879925 (Reactome)
High affinity

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

p(Y593,628)-Bc		ArrowR-HSA-879907 (Reactome)
High affinity

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

p(Y593,628)-Bc		R-HSA-879934 (Reactome)
High affinity

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

p(Y593,628)-Bc		R-HSA-909738 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2		ArrowR-HSA-879942 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2		R-HSA-879907 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2		R-HSA-879910 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2		R-HSA-913451 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc,

inactive JAK2		mim-catalysisR-HSA-879910 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc. activated

JAK2:STAT5		ArrowR-HSA-879930 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc. activated

JAK2:STAT5		R-HSA-879909 (Reactome)
High affinity

binding complex dimers of cytokine receptors using Bc. activated

JAK2:STAT5		mim-catalysisR-HSA-879909 (Reactome)
High affinity

binding complexes of interleukin receptors using the

Common beta chain		R-HSA-879942 (Reactome)
IL3:IL3RA:IL3RB:JAK2ArrowR-HSA-450031 (Reactome)
IL3:IL3RAArrowR-HSA-450074 (Reactome)
IL3:IL3RAR-HSA-450031 (Reactome)
IL3R-HSA-450074 (Reactome)
IL3RAR-HSA-450074 (Reactome)
IL3RB:JAK2ArrowR-HSA-879937 (Reactome)
IL3RB:JAK2R-HSA-450031 (Reactome)
IL3RB:JAK2R-HSA-913370 (Reactome)
IL3RB:JAK2R-HSA-913371 (Reactome)
IL5 homodimer:IL5RA:Common beta chain:JAK2ArrowR-HSA-913370 (Reactome)
IL5 homodimer:IL5RAArrowR-HSA-913456 (Reactome)
IL5 homodimer:IL5RAR-HSA-913370 (Reactome)
IL5 homodimerArrowR-HSA-913446 (Reactome)
IL5 homodimerR-HSA-913456 (Reactome)
IL5R-HSA-913446 (Reactome)
IL5RAR-HSA-913456 (Reactome)
Interleukin

receptor complexes with activated

Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks		ArrowR-HSA-508247 (Reactome)
Interleukin receptor

compexes with activated

Shc:GRB2:GAB2		ArrowR-HSA-453104 (Reactome)
Interleukin receptor

compexes with activated

Shc:GRB2:GAB2		R-HSA-912527 (Reactome)
Interleukin receptor

complexes with activated

SHC1:GRB2:SOS1		ArrowR-HSA-453111 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP1,2		ArrowR-HSA-913374 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP1		R-HSA-913424 (Reactome)
Interleukin receptor

complexes with activated

SHC1:SHIP:GRB2		ArrowR-HSA-913424 (Reactome)
Interleukin receptor

complexes with activated

Shc:GRB2:p-GAB2		ArrowR-HSA-912527 (Reactome)
Interleukin receptor

complexes with activated

Shc:GRB2:p-GAB2		R-HSA-508247 (Reactome)
Interleukin receptor

complexes with

activated SHC1		R-HSA-453104 (Reactome)
Interleukin receptor

complexes with

activated SHC1		R-HSA-453111 (Reactome)
Interleukin receptor

complexes with

activated SHC1		R-HSA-913374 (Reactome)
JAK2R-HSA-879937 (Reactome)
K48polyUbR-HSA-912627 (Reactome)
PRKACAmim-catalysisR-HSA-913451 (Reactome)
PTPN11R-HSA-914022 (Reactome)
PTPN6,PTPN11R-HSA-909738 (Reactome)
R-HSA-450031 (Reactome) The alpha subunit of the IL3 receptor binds IL 3 with low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008). Covalent linkage of the receptor subunits is required for receptor signalling (Stomski et al. 1996).
R-HSA-450074 (Reactome) The Interleukin-3 receptor alpha subunit (IL3Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (53 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Kitamura et al. 1991). It binds interleukin-3 with low affinity, and is not capable of signaling by itself.
R-HSA-452102 (Reactome) The STAT5a and STAT5b forms are encoded by 2 closely-related genes. They are thought to be present largely as monomers in unstimulated cells but rapidly form homo- and hetero-dimers upon stimulation (Cella et al. 1998). Tyrosine phosphorylation of STAT monomers allows dimers to form through reciprocal phosphotyrosine-SH2 interactions. The dimers translocate to the nucleus and bind to STAT-specific DNA-response elements of target genes to induce gene transcription (Baker et al.2007). STAT5a/b homo- and hetero-tetramers have also been shown to occur downstream of IL-2 and may have a distinct or expanded target repertoire from STAT5a/b dimers. Although STAT5a and STAT5b are highly homologous at the DNA and protein levels, each has unique functions, as demonstrated by studies comparing mice lacking one isoform or the other. However, it is also known that STAT5a and STAT5b share a number of functions and that the phenotype of mice lacking both STAT5a and STAT5b is more severe than those lacking either one individually, which suggest that there may be some redundancy or that they cooperate in order to achieve the full spectrum of STAT5-dependent activities (Moriggl et al. 1999, Teglund et al. 1998).
R-HSA-453104 (Reactome) Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000).
R-HSA-453111 (Reactome) Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway.
R-HSA-507937 (Reactome) STAT5A and STAT5B dimers bind to similar core gamma-interferon activated sequence (GAS) motifs (Soldaini et al., 2000). STAT5a/b also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. Genes that are regulated by STAT5 include IL2RA (John et al. 1996), TNFSF11 (RANKL), Connexin-26 (GJB2) and Cyclin D1 (Hennighausen & Robinson, 2005). A comprehensive listing of hepatic STAT5b regulated genes is available from microarray/STAT5b knockout mice (Clodfelter et al. 2006), and similarly for STAT5-dependent genes regulated by the GH receptor (Rowland et al. 2005, Barclay et al. 2011).
R-HSA-508247 (Reactome) Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain.
R-HSA-879907 (Reactome) Phosphorylation of the receptor common beta chain (Bc) creates binding sites for proteins that trigger subsequent signaling cascades (Pawson & Scott, 1997). The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One site is Y766 (numbered as Y750 by Sakamaki et al. 1992 and many other publications). Phosphorylation of Bc in response to GM-CSF/IL3 is observed at low temperatures (4 degrees C) that prevent the phosphorylation of other proteins, suggesting that the kinase responsible is likely to be physically associated with the receptor complex prior to stimulation (Miyajima et al. 1993). JAK2 is activated in response to IL-3, IL-5 and GM-CSF but signaling via JAK/STAT is not dependent on Bc tyrosine phosphorylation (Okuda et al. 1997). Based on these observations and the role of JAK1/3 in IL-2 signaling, JAK2 is believed to be the most likely candidate responsible for the phosphorylation of Bc (Guthridge et al. 1998). To represent the possible phosphorylation of Bc by kinases other than JAK2, this reaction includes receptor complexes with both active and inactive JAK2. Phosphorylation is represented only where this is necesssary for subsequent signaling; phosphorylation at other positions is probable.
R-HSA-879909 (Reactome) JAK2 phosphorylates STAT5; phosphorylated STAT5 dimerizes and translocates to the nucleus (Darnell et al., 1994), binds DNA and activates target genes including c-fos, pim-1, oncostatin M, and Id-1 (Mui et al. 1996). STAT5 activation is believed to be the primary signaling mechanism for Bc (Ihle, 2001).
R-HSA-879910 (Reactome) JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.

Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation.
R-HSA-879914 (Reactome) IL3 stimulation induces rapid and transient tyrosine-phosphorylation of Vav and the binding of Vav to Tec kinase through Tec homology domains. (Machide et al. 1995). Vav1 and Tec were seen to associate into a complex with the activated prolactin receptor (Kline et al. 2001). These reports were interpreted as Tec enhancing Vav GEF activity, but it has been suggested that Vav might contribute to Tec activation in T cell signaling (Reynolds et al. 2002). Tec kinases generally require PI3K-dependent membrane translocation and phosphorylation of the kinase domain, often by an Src family kinase, for activation (Takesono et al. 2002).
R-HSA-879917 (Reactome) Cbl is constitutively associated with Grb2 in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain can bind the adaptor protein CRKL.

Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998).
Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).

Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997).
R-HSA-879925 (Reactome) IL-3, IL-5 and GM-CSF all induce tyrosine phosphorylation of Shc (Dorsch et al. 1994). Three sites are known to mediate specific downstream associations; tyrosine Y427 (Salcini et al. 1994) mediates the subsequent association of Shc with Grb2 (Salcini et al. 1994). The identity of the kinase is unknown. Y349 and Y350 phosphorylation is not required for Ras-MAPK signaling but are involved in IL-3-induced cell survival (Gotoh et al. 1996).
Residue numbering used here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references given here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996.
R-HSA-879930 (Reactome) Activated JAK2 binds to unphosphorylated STAT5; cytokine treatment of cells leads to JAK2 activation and promotes binding of JAK2 to unphosphorylated STAT5.


STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004).


Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc).
The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000).
R-HSA-879934 (Reactome) Upon receptor activation, Shc is recruited to the receptor complex, where it becomes tyrosine phosphorylated. The recruitment of Shc is mediated by Y593 (Y577 in the mature peptide) of the common beta chain (Bc), which binds the PTB domain of Shc (Pratt et al. 1996). Phosphorylated Shc interacts with Grb2 within a Grb2:Gab2 complex, promoting tyrosine phosphorylation of Gab2. The p85 subunit of PI3Kinases associates with phosphorylated Gab, and this induces activation of the catalytic p110 PI3K subunit leading to activation of Akt kinase, thereby regulating cell survival and/or proliferation.
R-HSA-879937 (Reactome) JAK2 associates with IL3 reecptor beta chain (IL3RB) better known as the cytokine recetpor common beta chain (Bc). This association was not found to be dependent upon, or influenced by, the presence of GM-CSF or the GM-CSF receptor alpha chain, suggesting that JAK2 and Bc may be constitutively associated (Quelle et al. 1994).
R-HSA-879942 (Reactome) Upon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).

The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes.
R-HSA-909738 (Reactome) The common beta chain (Bc) has at least at least one direct binding site for SHP-1/SHP-2 (PTPN6/PTPN11). The SH2 domains of SHP1 and SHP2 associate with Y628 of Bc following IL-3 stimulation (Pei et al. 1994, Bone et al. 1997). SHPs act as regulators of signaling. SHP1 is thought to be a negative regulator of growth that terminates signals. Binding of SHP1 to EpoR leads to SHP1 activation and dephosphorylation of JAK2, terminating proliferative signals (Klingmuller et al. 1995). SHP1 has also been shown to interact directly and dephosphorylate JAK2 (Jiao et al. 1996). Although SHP-2 competes for the same binding site, it is thought to be a positive modulator. SHP2 associates with JAK1/2 and is phosphorylated at Y304 by these kinases, creating a GRB2 recognition motif (Yin et al. 1997). IL-3 induces the phosphorylation of SHP2 and its association with Grb2 (Welham et al. 1994). SHP2 could thereby act as an adaptor between Bc and Grb2 leading to activation of the ras/mitogen-activated protein kinase pathway. SHP2 can also associate with the p85 subunit of phosphatidylinositol 3-kinase (Welham et al. 1994) so SHP2 may also regulate this pathway.
R-HSA-912527 (Reactome) Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000).
R-HSA-912627 (Reactome) Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008).
R-HSA-912629 (Reactome) Cbl is tyrosine phosphorylated following stimulation with IL-3 (Anderson et al. 1997) and GM-CSF (Odai et al. 1995). Cbl may be phosphorylated prior to this IL-3 stimulated tyrosyl phosphorylation (Park et al. 1998). The kinase responsible for Cbl phosphorylation may be dependent on cell type; Fyn is demonstrated to have the ability to phosphorylate Cbl (Hunter et al. 1999), other candidates include Hck, Lyn (Hunter et al. 1999) and Syk (Park et al. 1998).

Tyrosines 700, 731 and 774 are the major sites of Cbl phosphorylation by non-receptor protein tyrosine kinases, with none showing any particular specificity for sites (Tsygankov et al. 2001). Fyn was observed to be constitutively associated with Cbl in lysates of several different cell types including the interleukin-3-dependent murine myeloid cell line 32Dcl3, and the prolactin-dependent rat thymoma cell line Nb2. Cbl phosphorylation at Y731 is postulated to provide an additional interaction between Cbl and the SH2 domain of p85-PI3K (Hunter et al. 1999). Cbl-p85 association increases in activated cells (Panchamoorthy et al. 1996). Expression of a Cbl Y731F mutant which abolishes binding of Cbl to p85 markedly increased levels of p85-PI3K (Dufour et al. 2008). Cbl-p85 binding negatively regulates PI3K activity (Fang et al. 2001); Cbl phosphorylation increased PI3K ubiquitination and proteasome degradation (Dufour et al. 2008). Cbl association with members of the Crk family is mediated by phosphorylation of Y700 and Y774 (Andoniou et al. 1996), binding with Vav is mediated by Y770 (Marengere et al 1997).
R-HSA-912724 (Reactome) Cbl binds B-cell linker protein, a molecular scaffold bridging Syk to downstream signaling pathways by recruiting signaling molecules, such as Btk, phospholipase C gamma 2, Vav, and Grb2 to the cell membrane to form a signalosome complex. Cbl is believed to negatively regulate signaling from this complex. Consistent with this, Cbl inactivation reverses a number of critical defects in early B cell differentiation seen in BLNK-deficient mice (Song et al. 2007).
R-HSA-912727 (Reactome) Cbl and Vav interact in thymocytes and peripheral T cells (Marengere et al. 1997). Cbl phosphorylated at Y700 binds Vav1 in 293T cells, leading to Vav ubiquitinylation and proteolytic degradation.
R-HSA-912734 (Reactome) Cbl has been identified in ternary complexes with CRKL and C3G (RAPGEF1)(Reedquist et al. 1996) a Rap1 GEF, suggesting a role for Cbl in linking cytokine stimulation to Rap1 activation. Consistent with this, stimulation of NB-4 promyelocytic cells by IFN-gamma causes tyrosine phosphorylation and association of Cbl with CRKL followed by activation of Rap1 (Alsayed et al. 2000) and tyrosine phosphorylation of Cbl and its association with CRKL correlated with an increase in Rap 1 activity in anergic T cells (Boussiotis et al. 1997).
R-HSA-912757 (Reactome) The common beta chain (Bc), binds 14-3-3 zeta at a site that requires phosphorylation of Serine 585 (Stomski et al. 1999). Bc modifications that prevent Ser-585 phosphorylation do not recruit 14-3-3 zeta (Guthridge et al. 2000).
R-HSA-912790 (Reactome) The Crk adapter protein family is comprised of Crk-I and Crk-II, alternatively spliced products of a single gene with differing biological functions, and Crk-L, a distinct Crk-like gene product. Cbl is the dominant phosphoprotein associated with Crk in activated lymphocytes. In vitro binding indicates that the Crk SH2 domain binds Y774 of Cbl (Reedquist et al. 1996), leaving the SH3 domain of Crk free to interact with other SH3 domain-associated proteins.
R-HSA-913360 (Reactome) The GM-CSF receptor alpha subunit has a single transmembrane domain, a glycosylated extracellular domain and a short (54 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Gearing et al. 1989). It binds GM-CSF with a relatively low affinity, and is not capable of signaling. The cytoplasmic domain of the alpha chain appears to be critical for GM-CSF signaling (Matsuguchi et al. 1997).
R-HSA-913370 (Reactome) The alpha subunit of the IL5 receptor binds IL-5 with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex may bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008).
R-HSA-913371 (Reactome) The alpha subunit of the GM-CSF receptor binds GM-CSF with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of GM-CSF with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008).
R-HSA-913374 (Reactome) SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
R-HSA-913424 (Reactome) Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
R-HSA-913446 (Reactome) Human IL-5 is a disulphide-linked homodimer with 115 amino-acid residues in each chain.
R-HSA-913451 (Reactome) GM-CSF and IL-3 application lead to Ser-585 phosphorylation of the Common beta chain (Bc) shared with the IL-3 and IL-5 receptors (Stomski et al. 1999, Guthridge et al. 2000). PKA was identified as capable of phosphorylating Bc at S585 (Guthridge et al. 2000).
R-HSA-913456 (Reactome) The Interleukin-5 receptor alpha subunit (IL5Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (58 amino acids) cytoplasmic tail, containing no tyrosine kinase domain. It binds IL-5 with a relatively low affinity and is not capable of signaling by itself. The alpha subunit has alternatively spliced soluble forms that are capable of binding IL-5 and act as natural antagonists of IL-5 signaling. The cytoplasmic domain of the alpha chain appears to be critical for IL-5 signaling (Takaki et al. 1993). IL5R alpha chain was found to be constitutively associated with JAK2 (Ogata et al. 1998); the same study found that JAK1 was constitutively associated with Bc, though the consensus is that JAK2 is associated with Bc.
R-HSA-914022 (Reactome) SHP2 can associate with GRB2 (Stein-Gerlach et al. 1995). IL-3 induces the phosphorylation of SHP2 and its association with GRB2 (Welham et al. 1994). SHP2 may act as a scaffold protein to recruit other signaling molecules, e.g. SHP2 was reported to link GRB2 to the receptor tyrosine kinase c-kit (Tauchi et al. 1994).
R-HSA-914036 (Reactome) Synthetic phosphopeptides based on Bc were dephosphorylated by SHP1 and SHP2, peptides phosphorylated at Y628 were the best substrate followed by those phosphorylated at Y766.
R-HSA-914182 (Reactome) Immunoprecipitation and kinase activity experiments demonstrated that Ser-585 phosphorylation of the common beta chain (Bc) was required for activation of PI3K activity in response to IL-3 and co-precipitation of Bc, 14-3-3 zeta and the p85 subunit of Class 1A PI3 kinases (Guthridge et al. 2000). Subsequent experiments confirmed that Ser-585 phosphorylation and PI3K activation are required to promote cell survival in response to GM-CSF, but not for proliferation responses, and that this mechanism is independent of Bc tyrosine phosphorylation (Guthridge et al. 2004). This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors; the other involves Bc tyrosine-593 phosphorylation-mediated recruitment of SHC1, GRB2 and GAB2.
R-HSA-921155 (Reactome) Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000).
RAPGEF1R-HSA-912734 (Reactome)
SHC1R-HSA-879934 (Reactome)
SHIP1,2R-HSA-913374 (Reactome)
SHP2:GRB2ArrowR-HSA-914022 (Reactome)
STAT5R-HSA-879930 (Reactome)
TEC:VAV1ArrowR-HSA-879914 (Reactome)
TECR-HSA-879914 (Reactome)
Tyrosine kinases

that phosphorylate the Common beta

chain		mim-catalysisR-HSA-879907 (Reactome)
VAV1R-HSA-879914 (Reactome)
VAV1R-HSA-912727 (Reactome)
YWHAZR-HSA-912757 (Reactome)
p(Y700,731,774)-CBL:CRK:RAPGEF1ArrowR-HSA-912734 (Reactome)
p(Y700,731,774)-CBL:CRKArrowR-HSA-912790 (Reactome)
p(Y700,731,774)-CBL:CRKR-HSA-912734 (Reactome)
p(Y700,731,774)-CBL:VAV1ArrowR-HSA-912727 (Reactome)
p-STAT5 dimerArrowR-HSA-452102 (Reactome)
p-STAT5 dimerArrowR-HSA-507937 (Reactome)
p-STAT5 dimerR-HSA-507937 (Reactome)
p-STAT5A/BArrowR-HSA-921155 (Reactome)
p-STAT5A/BR-HSA-452102 (Reactome)
p-Y700,Y731,Y774-CBLR-HSA-912724 (Reactome)
p-Y700,Y731,Y774-CBLR-HSA-912727 (Reactome)
p-Y700,Y731,Y774-CBLR-HSA-912790 (Reactome)
p85-containing Class 1A PI3KsR-HSA-508247 (Reactome)
p85-containing Class 1A PI3KsR-HSA-879917 (Reactome)
p85-containing Class 1A PI3KsR-HSA-914182 (Reactome)
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