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

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1, 222, 231, 75185, 1135, 385535-373933, 3493253, 543395446, 4942, 4345-481450, 5128, 2985212, 13144-640, 4124-2623, 2430, 314423, 274119-214015-179, 10cytosolnucleoplasmp(Y700,731,774)-CBLSHP-2/SHP-1IL5 homodimer:IL5RA:Common beta chain:JAK2ATPInterleukin receptor complexes with activated Shc:GRB2:p-GAB2ATPCBLGM-CSF/IL-3/IL-5 receptor common beta chainIL3RAp(Y700,731,774)-CBL:CRK:RAPGEF1High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1Granulocyte-macrophage colony-stimulating factorRAPGEF1Interleukin receptor complexes with activated SHC1:GRB2:SOS1Phospho (2 sites) RAF1B-cell linker protein:p(Y700,731,774)-CBLFYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsInterleukin receptor complexes with activated SHC1High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc:SHC1Tyrosine kinases that phosphorylate the Common beta chainK48-polyubiquitinHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-BcHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zetaADPSTAT5 dimersTECIL5GM-CSF:GM-CSF receptor alpha subunit:Common beta chain:JAK2High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsH-Ras-GTPGM-CSF receptor alpha subunitATPInterleukin receptor compexes with activated Shc:GRB2:GAB2GRB2:SOS1H-Ras-GDPIL3:IL3RAHigh affinity binding complex dimers of cytokine receptors using Bc, activated JAK2TEC:VAV1VAV1SHC1High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc:SHP1, SHP2IL5 homodimer:IL5RACRKATPp85-containing Class 1A PI3KsIL5 homodimerADPInterleukin receptor complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3KsB-cell linker proteinInterleukin receptor complexes with activated SHC1:SHIP1IL5RAHigh affinity binding complexes of interleukin receptors using the Common beta chainADPADPSHP2:GRB2p(Y700,731,774)-CBL:CRK14-3-3 zetaHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc:SHP1, SHP2IL3RA:IL3:Common beta chain:JAK2SHIP1,2STAT5p-STAT5Interleukin receptor complexes with activated SHC1:SHIP:GRB2High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-BcSTAT5 dimersATPSHP2ADPGRB2:GAB2JAK2p(Y700,731,774)-CBL:VAV1High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2:STAT5FYN-like kinasesIL3GDPHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing Class 1A PI3KsCommon beta chain:JAK2Interleukin receptor complexes with activated SHC1:SHIP1,2GRB2FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3KsGTPHigh affinity binding complex dimers of cytokine receptors using Bc, activated JAK2:p-STAT5GM-CSF:GM-CSF receptor alpha subunitRas:GTP:Phospho (2 sites) RAF1cAMP-dependent protein kinase, beta-catalytic subunit


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.

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Bibliography

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History

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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
14-3-3

zeta

ProteinP63104 (UniProt)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
B-cell linker

protein

ProteinQ8WV28 (UniProt)
B-cell linker protein:p

(Y700,731,774)-CBL

ComplexREACT_24555 (Reactome)
CBL ProteinP22681 (UniProt)
CRK ProteinREACT_24469 (Reactome)
Common beta

chain:JAK2

ComplexREACT_24165 (Reactome)
FYN-like kinases ProteinREACT_24391 (Reactome)
FYN-like kinases:

CBL:GRB2:p85- containing Class 1A PI3Ks

ComplexREACT_24661 (Reactome)
FYN-like kinases:p

(Y731)-CBL:GRB2: Ubiquitinated p85- containing Class 1A PI3Ks

ComplexREACT_24386 (Reactome)
FYN-like kinases:p

(Y731)-CBL:GRB2: p85-containing Class 1A PI3Ks

ComplexREACT_24228 (Reactome)
GDP Metabolite17552 (ChEBI)
GM-CSF receptor

alpha subunit

ProteinP15509 (UniProt)
GM-CSF/IL-3/IL-5

receptor common beta chain

ProteinP32927 (UniProt)
GM-CSF:GM-CSF

receptor alpha subunit

ComplexREACT_24102 (Reactome)
GM-CSF:GM-CSF

receptor alpha subunit:Common beta chain:JAK2

ComplexREACT_24858 (Reactome)
GRB2 ProteinP62993-1 (UniProt)
GRB2:GAB2 ComplexREACT_24714 (Reactome)
GRB2:SOS1 ComplexREACT_4435 (Reactome)
GTP Metabolite15996 (ChEBI)
Granulocyte-

macrophage colony- stimulating factor

ProteinP04141 (UniProt)
H-Ras-GDP ComplexREACT_24031 (Reactome)
H-Ras-GTP ComplexREACT_24217 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, activated JAK2

ComplexREACT_24626 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, activated JAK2:p-STAT5

ComplexREACT_24628 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc

ComplexREACT_24222 (Reactome)
High affinity binding

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

ComplexREACT_24266 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:SHC1

ComplexREACT_24884 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)- Bc:p(427,349,350)- SHC1

ComplexREACT_24225 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc: SHP1, SHP2

ComplexREACT_24560 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc: SHP1, SHP2

ComplexREACT_24887 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2

ComplexREACT_24738 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc

ComplexREACT_24147 (Reactome)
High affinity binding

complex dimers of cytokine receptors using Bc. activated JAK2:STAT5

ComplexREACT_24047 (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

ComplexREACT_24243 (Reactome)
High affinity binding

complexes of interleukin receptors using the Common beta chain

ComplexREACT_24474 (Reactome)
IL3 ProteinP08700 (UniProt)
IL3:IL3RA ComplexREACT_24866 (Reactome)
IL3RA ProteinP26951 (UniProt)
IL3RA:IL3:Common

beta chain:JAK2

ComplexREACT_24229 (Reactome)
IL5 ProteinP05113 (UniProt)
IL5 homodimer ComplexREACT_24473 (Reactome)
IL5 homodimer:

IL5RA

ComplexREACT_24270 (Reactome)
IL5 homodimer:

IL5RA:Common beta chain:JAK2

ComplexREACT_24214 (Reactome)
IL5RA ProteinQ01344 (UniProt)
Interleukin receptor

compexes with activated Shc:GRB2:GAB2

ComplexREACT_24494 (Reactome)
Interleukin receptor

complexes with activated SHC1

ComplexREACT_24730 (Reactome)
Interleukin receptor

complexes with activated SHC1: GRB2:SOS1

ComplexREACT_24582 (Reactome)
Interleukin receptor

complexes with activated SHC1: SHIP1,2

ComplexREACT_24093 (Reactome)
Interleukin receptor

complexes with activated SHC1:SHIP1

ComplexREACT_24554 (Reactome)
Interleukin receptor

complexes with activated SHC1:SHIP: GRB2

ComplexREACT_24297 (Reactome)
Interleukin receptor

complexes with activated Shc:GRB2: p-GAB2:p85- containing Class 1 PI3Ks

ComplexREACT_24797 (Reactome)
Interleukin receptor

complexes with activated Shc:GRB2:p-GAB2

ComplexREACT_24779 (Reactome)
JAK2 ProteinO60674 (UniProt)
K48-polyubiquitin UnknownREACT_24769 (Reactome)
Phospho (2 sites)

RAF1

ProteinP04049 (UniProt)
RAPGEF1 ProteinQ13905 (UniProt)
Ras:GTP:Phospho (2

sites) RAF1

ComplexREACT_24177 (Reactome)
SHC1 ProteinP29353 (UniProt)
SHIP1,2 ProteinREACT_24095 (Reactome)
SHP-2/SHP-1 ProteinREACT_20250 (Reactome)
SHP2 ProteinQ06124 (UniProt)
SHP2:GRB2 ComplexREACT_24568 (Reactome)
STAT5 ProteinREACT_24211 (Reactome)
STAT5 dimers UnknownREACT_24109 (Reactome)
STAT5 dimers UnknownREACT_24289 (Reactome)
TEC ProteinP42680 (UniProt)
TEC:VAV1 ComplexREACT_24039 (Reactome)
Tyrosine kinases that

phosphorylate the Common beta chain

ComplexREACT_24291 (Reactome)
VAV1 ProteinP15498 (UniProt)
cAMP-dependent

protein kinase, beta- catalytic subunit

ProteinP22694 (UniProt)
p(Y700,731,774)-

CBL

ProteinP22681 (UniProt)
p(Y700,731,774)-

CBL:CRK

ComplexREACT_24612 (Reactome)
p(Y700,731,774)-

CBL:CRK:RAPGEF1

ComplexREACT_24589 (Reactome)
p(Y700,731,774)-

CBL:VAV1

ComplexREACT_24764 (Reactome)
p-STAT5 UnknownREACT_24299 (Reactome)
p85-containing

Class 1A PI3Ks

ComplexREACT_24162 (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

No annotated interactions

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