Interleukin-2 family signaling (Homo sapiens)

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1, 33, 3811, 16146246, 522, 5, 45, 49, 53...2, 5, 45, 49, 53...625, 608, 924, 2748348, 49, 6125, 267, 949, 615740, 476532, 51, 5942, 55, 656, 2817292921, 6213, 5456, 598, 937, 40nucleoplasmcytosolADPInterleukin receptorcomplexes withactivatedSHC1:GRB2:SOS1IL2 IL2 IL2RG GRB2-1 STAT5A IL2RA IL2RB IL2 JAK3 IL2 PIK3CA p-Y364,Y418,Y536-IL2RB p-Y-JAK1 IL2 PIK3CD IL2 IL21 PTK2Bp-Y-JAK1 STAT1 p-Y-SHC1 IL2RG:JAK3GRB2-1IL2 SOS1 INPPL1 JAK3 p-Y694-STAT5A IL2RA IL2RA IL2RG IL2 IL21R p-Y-SHC1 ATPATPSTAT4 IL2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 p-Y364,Y418,Y536-IL2RB p-Y-JAK3 p-Y-JAK1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 JAK3 IL21 JAK3 p-Y364,Y418,Y536-IL2RB SHC kinases in IL2signalingSTAT3 p-Y-JAK1 IL2RB p-Y701-STAT1 HAVCR2p-Y-JAK1 IL2RA IL2RA GRB2-1 p-Y364,Y418,Y536-IL2RB IL2:IL2RALGALS9GRB2-1 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 ADPJAK3 p-STAT5A, p-STAT5Bp-Y-SHC1 IL21IL2RG JAK3 IL21R Interleukin receptorcomplexes withactivated SHC1JAK3 IL2:IL2Rtrimer:p-JAK1:JAK3:SYKJAK1 IL21 p-Y-JAK1 PIK3R3 JAK1(p-Y694-STAT5A,p-Y699-STAT5B) IL21R HAVCR2 p-Y699-STAT5B JAK3 p-Y-JAK1 p-STAT5 dimerADPIL21R p-Y-JAK1 Interleukin receptorcomplexes withactivatedSHC1:SHIP1IL2 p-Y-SHC1 PTPN6 ATPp-Y-SHC1 IL2RA IL2RB InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3KsJAK3 Interleukin-15signalingSYK IL2 IL2RA IL2RG IL2RG IL21:IL21R:JAK1p-Y694-STAT5A High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL21:IL21R:JAK1:IL2RG:JAK3IL2RBINPP5D IL21 p-Y-SYK IL2RA IL2RG RAF/MAP kinasecascadeIL2RA ADPIL2 p-Y-GAB2 SHC1 p85-containing Class1A PI3KsIL21R:JAK1Interleukin-9signalingADPPIK3R2 GRB2-1 SOS1 IL2RG STAT5A PIK3R1 JAK3 p-Y-GAB2 PIK3R1 IL2RG GAB2 IL2RA IL2 p-Y694-STAT5A Interleukin receptorcomplexes withactivatedSHC1:SHIP:GRB2p-Y-JAK3 p-Y-JAK1 p-Y-PTK2B p-Y693-STAT4 STAT5 p-Y699-STAT5B IL21R IL2RA LGALS9 INPPL1 p-Y-JAK1 p-Y364,Y418,Y536-IL2RB ATPIL21 JAK3 JAK3:PYK2IL2 IL2RGp-Y364,Y418,Y536-IL2RB SHC1p-Y-JAK1 p-Y-JAK1 p-Y-JAK1 JAK1 p-Y699-STAT5B STAT5B JAK1 IL2RG p-Y364,Y418,Y536-IL2RB IL2RG IL2:IL2Rtrimerp-(Y338,392,510)betasubunit:p-JAK1:JAK3:STAT5IL2RA PTPN6 p-Y-JAK1 IL2RG IL2RAInterleukin receptorcomplexes withactivatedShc:GRB2:p-GAB2GRB2-1 IL2RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 p-Y-JAK1 JAK3:p-PYK2p-Y694-STAT5A IL2RB PIK3R2 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 IL21R ADPJAK3 p-Y-JAK1 IL2RB p-Y364,Y418,Y536-IL2RB IL2RG p-Y-JAK1 IL2RG IL2RB:JAK1JAK1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 STAT5B STAT4 PIK3R3 ATPIL2RB IL2RA IL2 IL2RA PIK3CD p-Y705-STAT3 ATPp-Y-JAK1 IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y693-STAT4,(p-Y694-STAT5A,p-Y699-STAT5B)IL2:IL2Rtrimer:p-JAK1:JAK3:p-SYKp-Y-SHC1 IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:STAT1,STAT3,STAT4,STAT5GRB2-1 IL2 IL2RG IL2p-Y699-STAT5B ATPJAK3 p-Y-JAK3 PTK2B SYKp-Y-SHC1 p-Y-SHC1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 p-STAT5 dimerIL2:IL2Rtrimerp-(Y338,Y392,Y510)betasubunit:p-JAK1:JAK3:p-STAT5IL2:IL2Rtrimer:p-JAK1:JAK3ADPp-Y364,Y418,Y536-IL2RB p-Y-JAK1 IL2RG Interleukin receptorcomplexes withactivatedSHC1:SHIP1,2IL2RG JAK3 IL2RA IL2 STAT5A,STAT5BINPP5D STAT1 IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3IL2RA PIK3CB ADPLCK JAK1 IL2 GRB2-1:SOS1IL2RA IL2:IL2Rtrimerp-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHCSTAT5 IL2:IL2Rtrimerp-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHCIL2:IL2RA:IL2RB:JAK1STAT3 IL2RG IL2RG p-Y364,Y418,Y536-IL2RB IL2 IL2RA GRB2-1 JAK1 ATPIL2:IL2R trimerp-(Y338,392,510)betasubunit:p-JAK1:JAK3JAK3 IL2RG JAK3 p-Y364,Y418,Y536-IL2RB Interleukin receptorcompexes withactivatedShc:GRB2:GAB2JAK3 IL2RG SHIP1,2PIK3CB p-Y364,Y418,Y536-IL2RB GRB2:GAB2GAB2 IL2:IL2Rtrimer:JAK1:JAK3STAT1,STAT3,STAT4,STAT5JAK3 JAK3 p-Y-JAK1 PIK3CA p-Y364,Y418,Y536-IL2RB p-Y-SHC1 HAVCR2:LGALS9JAK3 IL2RG JAK3 JAK3IL2RG 15, 36394, 10, 18, 20, 22...19, 23, 443912, 6439


Description

The interleukin-2 family (also called the common gamma chain cytokine family) consists of interleukin (IL)2, IL9, IL15 and IL21. Although sometimes considered to be within this family, the IL4 and IL7 receptors can form complexes with other receptor chains and are represented separately in Reactome. Receptors of this family associate with JAK1 and JAK3, primarily activating STAT5, although certain family members can also activate STAT1, STAT3 or STAT6. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 451927
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Ray, KP

Quality Tags

Ontology Terms

 

Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
101637view11:50, 1 November 2018ReactomeTeamreactome version 66
101173view21:37, 31 October 2018ReactomeTeamreactome version 65
100699view20:09, 31 October 2018ReactomeTeamreactome version 64
100249view16:54, 31 October 2018ReactomeTeamreactome version 63
99801view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94491view08:55, 14 September 2017MkutmonReactome release 61
87864view12:07, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86385view09:16, 11 July 2016ReactomeTeamreactome version 56
83330view10:48, 18 November 2015ReactomeTeamVersion54
81481view13:01, 21 August 2015ReactomeTeamVersion53
76959view08:24, 17 July 2014ReactomeTeamFixed remaining interactions
76664view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75993view10:05, 11 June 2014ReactomeTeamRe-fixing comment source
75696view11:03, 10 June 2014ReactomeTeamReactome 48 Update
75052view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74696view08:46, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-Y694-STAT5A,p-Y699-STAT5B) R-HSA-1295524 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:GAB2ComplexR-HSA-912522 (Reactome)
HAVCR2 ProteinQ8TDQ0 (Uniprot-TrEMBL)
HAVCR2:LGALS9ComplexR-HSA-5340393 (Reactome)
HAVCR2ProteinQ8TDQ0 (Uniprot-TrEMBL)
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)
IL21 ProteinQ9HBE4 (Uniprot-TrEMBL)
IL21:IL21R:JAK1:IL2RG:JAK3ComplexR-HSA-9006846 (Reactome)
IL21:IL21R:JAK1ComplexR-HSA-9005977 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:STAT1,STAT3,STAT4,STAT5ComplexR-HSA-9006875 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y693-STAT4,(p-Y694-STAT5A,p-Y699-STAT5B)ComplexR-HSA-9006869 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3ComplexR-HSA-9006856 (Reactome)
IL21ProteinQ9HBE4 (Uniprot-TrEMBL)
IL21R ProteinQ9HBE5 (Uniprot-TrEMBL)
IL21R:JAK1ComplexR-HSA-9006858 (Reactome)
IL2:IL2R

trimer p-(Y338,392,510) beta

subunit:p-JAK1:JAK3:STAT5
ComplexR-HSA-452107 (Reactome)
IL2:IL2R

trimer

p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC
ComplexR-HSA-452095 (Reactome)
IL2:IL2R

trimer

p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC
ComplexR-HSA-453099 (Reactome)
IL2:IL2R

trimer p-(Y338,Y392, Y510) beta

subunit:p-JAK1:JAK3:p-STAT5
ComplexR-HSA-507943 (Reactome)
IL2:IL2R trimer:JAK1:JAK3ComplexR-HSA-450080 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:SYKComplexR-HSA-508449 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:p-SYKComplexR-HSA-508438 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3ComplexR-HSA-451920 (Reactome)
IL2:IL2R trimer

p-(Y338,392,510) beta

subunit:p-JAK1:JAK3
ComplexR-HSA-452119 (Reactome)
IL2:IL2RA:IL2RB:JAK1ComplexR-HSA-450065 (Reactome)
IL2:IL2RAComplexR-HSA-538993 (Reactome)
IL2ProteinP60568 (Uniprot-TrEMBL)
IL2RA ProteinP01589 (Uniprot-TrEMBL)
IL2RAProteinP01589 (Uniprot-TrEMBL)
IL2RB ProteinP14784 (Uniprot-TrEMBL)
IL2RB:JAK1ComplexR-HSA-451905 (Reactome)
IL2RBProteinP14784 (Uniprot-TrEMBL)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL2RG:JAK3ComplexR-HSA-451911 (Reactome)
IL2RGProteinP31785 (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)
Interleukin-15 signalingPathwayR-HSA-8983432 (Reactome) The high affinity Interleukin-15 receptor is a heterotrimer of Interleukin-15 receptor subunit alpha (IL15RA), Interleukin-2 receptor subunit beta (IL2RB, CD122) and Cytokine receptor common subunit gamma (IL2RG, CD132). IL2RB and IL2RG are also components of the Interleukin-2 (IL2) receptor. Treatment of human T cells with Interleukin-15 (IL15) results in tyrosine phosphorylation of Tyrosine-protein kinase JAK1 (JAK1, Janus kinase 1) and Tyrosine-protein kinase JAK3 (JAK3, Janus kinase 3) (Johnston et al. 1995, Winthrop 2017). IL15 can signal by a process termed 'trans presentation', where IL15 bound by IL15 on one cell is trans-presented to IL2RB:IL2RG on another cell (Dubois et al. 2002) but can also participate in more 'traditional' cis signaling (Wu et al. 2008, Mishra et al. 2014) where all the three receptors are present on the same cell. Stimulation of lymphocytes by IL15 release MAPK activation through GAB2/SHP2/SHC (GRB2-associated-binding protein 2/Tyrosine-protein phosphatase non-receptor type 11/SHC transforming protein 1 or 2) cascade activation (Gadina et al. 2000).
Interleukin-9 signalingPathwayR-HSA-8985947 (Reactome) Interleukin 9 (IL9) binds interleukin 9 receptor a chain (IL9R) and the interleukin 2 receptor common gamma chain (IL2RG) to initiate IL9 signaling downstream cascade. IL9R colocalize with Interleukin 2 receptor α chain and MHC molecules in lipid rafts of human T lymphoma cells (Nizsalóczki et al. 2014). IL2RG is essential for IL9 dependent growth signal transduction (Kimura et al. 1995). IL9R (glycoprotein of 64 kDa) has saturable and specific binding sites with a Kd of 100 pM (Renauld et al. 1992). The activated IL9R complex recruits tyrosine kinase proteins from the Janus kinase (JAK) family: JAK1 (JAK1) and JAK3 (JAK3) for subsequent activation of the Signal transducer and activator of transcription (STAT) factors STAT1, STAT3 and STAT5. The activated STATs form STAT5 dimers and STAT1:STAT3 heterodimers (Neurath & Finotto 2016, Li & Rostami 2010).
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK1ProteinP23458 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
JAK3:PYK2ComplexR-HSA-508512 (Reactome)
JAK3:p-PYK2ComplexR-HSA-508510 (Reactome)
JAK3ProteinP52333 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LGALS9 ProteinO00182 (Uniprot-TrEMBL)
LGALS9ProteinO00182 (Uniprot-TrEMBL)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PTK2B ProteinQ14289 (Uniprot-TrEMBL)
PTK2BProteinQ14289 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
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).
SHC kinases in IL2 signalingComplexR-HSA-453105 (Reactome)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SHIP1,2ComplexR-HSA-913467 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1,STAT3,STAT4,STAT5ComplexR-HSA-9006868 (Reactome)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT4 ProteinQ14765 (Uniprot-TrEMBL)
STAT5 R-HSA-1295523 (Reactome)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5A,STAT5BComplexR-HSA-452094 (Reactome)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
p-STAT5 dimerComplexR-HSA-507919 (Reactome)
p-STAT5 dimerComplexR-HSA-508012 (Reactome)
p-STAT5A, p-STAT5BComplexR-HSA-507929 (Reactome)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-JAK3 ProteinP52333 (Uniprot-TrEMBL)
p-Y-PTK2B ProteinQ14289 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y-SYK ProteinP43405 (Uniprot-TrEMBL)
p-Y364,Y418,Y536-IL2RB ProteinP14784 (Uniprot-TrEMBL)
p-Y693-STAT4 ProteinQ14765 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y701-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p85-containing Class 1A PI3KsComplexR-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 as a reagent experimentally and measured by p85-Abs.The other forms are rarely used or determined experimentally. Also note that Class 1A PI3Ks may not be the most relevant physiologically in some cell types (e.g. T cells). There are five variants of the p85 regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta, and p55gamma. There are also three variants of the p110 catalytic subunit designated p110alpha, beta, or gamma catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two are expressed by Pik3r2 and Pik3r3, respectively). The most highly expressed regulatory subunit is p85alpha. All three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110alpha, p110beta and p110gamma, respectively). The alpha and beta p110s are expressed in all cells, while p110gamma is expressed primarily in leukocytes. It has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110gamma subunits comprise the class IB PI3Ks, each is encoded by a single gene.

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-451942 (Reactome)
ADPArrowR-HSA-452097 (Reactome)
ADPArrowR-HSA-452100 (Reactome)
ADPArrowR-HSA-452122 (Reactome)
ADPArrowR-HSA-508282 (Reactome)
ADPArrowR-HSA-9006850 (Reactome)
ADPArrowR-HSA-9006870 (Reactome)
ADPArrowR-HSA-912527 (Reactome)
ATPR-HSA-451942 (Reactome)
ATPR-HSA-452097 (Reactome)
ATPR-HSA-452100 (Reactome)
ATPR-HSA-452122 (Reactome)
ATPR-HSA-508282 (Reactome)
ATPR-HSA-9006850 (Reactome)
ATPR-HSA-9006870 (Reactome)
ATPR-HSA-912527 (Reactome)
GRB2-1:SOS1R-HSA-453111 (Reactome)
GRB2-1R-HSA-913424 (Reactome)
GRB2:GAB2R-HSA-453104 (Reactome)
HAVCR2:LGALS9ArrowR-HSA-5340385 (Reactome)
HAVCR2R-HSA-5340385 (Reactome)
IL21:IL21R:JAK1:IL2RG:JAK3ArrowR-HSA-9006844 (Reactome)
IL21:IL21R:JAK1:IL2RG:JAK3R-HSA-9006850 (Reactome)
IL21:IL21R:JAK1ArrowR-HSA-9005980 (Reactome)
IL21:IL21R:JAK1R-HSA-9006844 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:STAT1,STAT3,STAT4,STAT5ArrowR-HSA-9006873 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:STAT1,STAT3,STAT4,STAT5R-HSA-9006870 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3:p-Y701-STAT1,p-Y705-STAT3,p-Y693-STAT4,(p-Y694-STAT5A,p-Y699-STAT5B)ArrowR-HSA-9006870 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3ArrowR-HSA-9006850 (Reactome)
IL21:IL21R:p-Y-JAK1:IL2RG:p-Y-JAK3R-HSA-9006873 (Reactome)
IL21R-HSA-9005980 (Reactome)
IL21R:JAK1R-HSA-9005980 (Reactome)
IL2:IL2R

trimer p-(Y338,392,510) beta

subunit:p-JAK1:JAK3:STAT5
ArrowR-HSA-452108 (Reactome)
IL2:IL2R

trimer p-(Y338,392,510) beta

subunit:p-JAK1:JAK3:STAT5
R-HSA-452097 (Reactome)
IL2:IL2R

trimer p-(Y338,392,510) beta

subunit:p-JAK1:JAK3:STAT5
mim-catalysisR-HSA-452097 (Reactome)
IL2:IL2R

trimer

p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC
ArrowR-HSA-452091 (Reactome)
IL2:IL2R

trimer

p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC
R-HSA-452100 (Reactome)
IL2:IL2R

trimer

p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC
ArrowR-HSA-452100 (Reactome)
IL2:IL2R

trimer p-(Y338,Y392, Y510) beta

subunit:p-JAK1:JAK3:p-STAT5
ArrowR-HSA-452097 (Reactome)
IL2:IL2R

trimer p-(Y338,Y392, Y510) beta

subunit:p-JAK1:JAK3:p-STAT5
R-HSA-919404 (Reactome)
IL2:IL2R trimer:JAK1:JAK3ArrowR-HSA-450063 (Reactome)
IL2:IL2R trimer:JAK1:JAK3R-HSA-451942 (Reactome)
IL2:IL2R trimer:JAK1:JAK3mim-catalysisR-HSA-451942 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:SYKArrowR-HSA-508292 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:SYKR-HSA-508282 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:SYKmim-catalysisR-HSA-508282 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3:p-SYKArrowR-HSA-508282 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3ArrowR-HSA-451942 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3R-HSA-452122 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3R-HSA-508292 (Reactome)
IL2:IL2R trimer:p-JAK1:JAK3mim-catalysisR-HSA-452122 (Reactome)
IL2:IL2R trimer

p-(Y338,392,510) beta

subunit:p-JAK1:JAK3
ArrowR-HSA-452122 (Reactome)
IL2:IL2R trimer

p-(Y338,392,510) beta

subunit:p-JAK1:JAK3
ArrowR-HSA-919404 (Reactome)
IL2:IL2R trimer

p-(Y338,392,510) beta

subunit:p-JAK1:JAK3
R-HSA-452091 (Reactome)
IL2:IL2R trimer

p-(Y338,392,510) beta

subunit:p-JAK1:JAK3
R-HSA-452108 (Reactome)
IL2:IL2RA:IL2RB:JAK1ArrowR-HSA-450027 (Reactome)
IL2:IL2RA:IL2RB:JAK1R-HSA-450063 (Reactome)
IL2:IL2RAArrowR-HSA-450054 (Reactome)
IL2:IL2RAR-HSA-450027 (Reactome)
IL2R-HSA-450054 (Reactome)
IL2RAR-HSA-450054 (Reactome)
IL2RB:JAK1ArrowR-HSA-451900 (Reactome)
IL2RB:JAK1R-HSA-450027 (Reactome)
IL2RBR-HSA-451900 (Reactome)
IL2RG:JAK3ArrowR-HSA-451895 (Reactome)
IL2RG:JAK3R-HSA-450063 (Reactome)
IL2RG:JAK3R-HSA-9006844 (Reactome)
IL2RGR-HSA-451895 (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)
JAK1R-HSA-451900 (Reactome)
JAK3:PYK2ArrowR-HSA-508513 (Reactome)
JAK3:PYK2R-HSA-508451 (Reactome)
JAK3:p-PYK2ArrowR-HSA-508451 (Reactome)
JAK3R-HSA-451895 (Reactome)
JAK3R-HSA-508513 (Reactome)
LGALS9R-HSA-5340385 (Reactome)
PTK2BR-HSA-508513 (Reactome)
R-HSA-450027 (Reactome) The crystal structure of the assembled IL2:IL2 receptor complex and experiments using isothermal titration calorimetry suggest that the complex of IL2 with IL2R alpha is likely to preferentially associate with IL2R bet (Rickert et al. 2004, Stauber et al. 2006). Binding of IL-2/IL-2R alpha to IL-2R beta significantly slows the dissociation of IL-2. However, the trimeric complex of IL-2:IL-2R alpha:IL-2R beta is incapable of signaling without participation of the gamma chain.
R-HSA-450054 (Reactome) The interleukin-2 receptor is a heterotrimer composed of interleukin-2 receptor alpha (IL2RA), beta (IL2RB) and gamma (IL2RG) subunits. Individually, IL2RA and IL2RB have low affinity for interleukin-2 (IL2); IL2RG has very low affinity. The IL2RA chain has a short cytoplasmic domain and consequently does not transmit an intracellular signal, but it binds IL-2 with high affinity and is required in vivo for detection of physiological IL-2 levels (Kd for IL-2RB/G = 10-9 M versus 10-11 M for IL-2RA/B/G, Takeshita et al. 1992). The crystal structure of the trimeric complex bound to IL2 suggests that the initiating event is the binding of IL2 to IL2R alpha (Wang et al. 2005). This captures IL2 at the cell surface and allows the recruitment of the beta and gamma subunits, which then participate in signal transduction. IL-2R alpha chains are expressed at much greater levels than the other receptor chains, usually 10-1000-fold higher compared with IL-2R beta or gamma (~1,000 sites/cell), which are usually expressed in equal numbers (Smith & Cantrell 1985). Recent single cell analysis methods have found that as the density of IL-2R alpha chains varies 1,000-fold from 100 to 100,000 sites/cell, the equilibrium dissociation constant of IL-2 binding varies to the same extent, from 100 pM to 100 fM, with the consequence that as the density of IL-2R alpha chains increases there is a marked improvement in IL-2 binding efficiency and thus signaling (Feinerman O et al. 2010). IL-2 binding to IL-2Ralpha is rapid on and rapid off.
R-HSA-450063 (Reactome) Recruitment of the IL-2R gamma chain forms a very stable quaternary complex, capable of signaling. The IL-2 gamma chain further retards IL-2 dissociation so that the rate of IL-2 dissociation from the complex is three times slower than the rate of internalization of the complex (t1/2 55= 45 min vs. 15 min). Therefore, the complex continues to signal as long as it remains on the cell surface.
R-HSA-451895 (Reactome) Cytokine receptor common gamma subunit (IL2RG, IL-2 receptor gamma chain, Gc) associates with Tyrosine-protein kinase JAK3 (JAK3). The carboxyl-terminal region of IL2RG is important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994) as well as the FERM domain in JAK3 (Zhou et al. 2001).
R-HSA-451900 (Reactome) Janus Kinase 1 (JAK1) constitutively associates with IL-2R beta.
R-HSA-451942 (Reactome) Receptor activation involves JAK1 and JAK3 as T-cells from mice lacking either kinase are unable to respond to cytokines that utilize the Common gamma chain (Rodig et al. 1998, Park et al. 1995). Naturally occurring JAK3 mutations prevent binding to the Interleukin-2 receptor, leading to severe immunodeficiency due to a lack of signaling (Macchi et al. 1995, Russell et al. 1995). Mechanistic models of receptor activation suggest that assembly of the quaternary receptor and the consequent proximity of JAK1 and JAK3, bound to the cytoplasmic domains of the beta and gamma chains, is the trigger for JAK activation (Ellery et al. 2000). JAK3 is thought to activate JAK1, as JAK3 does not require tyrosine phosphorylation to activate its kinase activity (Liu et al. 1997), and JAK3 has been demonstrated to phosphorylate JAK1 in response to IL-2 (Kawahara et al. 1995). JAK3 also becomes phosphorylated in response to IL-2 (Johnston et al. 1994), either by JAK1 trans-activation or by an indirect mechanism. The activated JAKs then phosphorylate critical tyrosine residues within IL2RB.
R-HSA-452091 (Reactome) Phosphorylation of IL2RB Y338 creates a binding site for the accessory protein SHC, which then becomes tyrosine phosphorylated and recruits the Grb2/Sos and Grb2:Gab2 complexes.
R-HSA-452097 (Reactome) STAT5 alpha and beta are recruited to the receptor complex and phosphorylated. JAK3 is believed to be responsible for the tyrosine phosphorylation of STAT5 in response to IL-2; it is not clear whether JAK1 is also involved (Lin & Leonard, 2000). Tyr-694 of STAT5a and Tyr-699 of STAT5b are required for IL-2 induced STAT5 activation (Lin et al. 1996). STAT5a and STAT5b are also known to be serine phosphorylated in lymphocytes activated by IL-2 but the funtion of this is unclear (Xue et al. 2002).
R-HSA-452100 (Reactome) Following IL2 stimulation of IL2R, Shc is known to be tyrosine phosphorylated (Zhu et al. 1994). The identity of the kinase is uncertain (Gesbert et al. 1998); JAK1 may be responsible but this has not been demonstrated, another candidate is Lck.

Following IL-3 treatment, Shc becomes tyrosyl phoshorylated at 3 sites, Y427 (Salcini et al. 1994), Y349 and Y350 (Gotoh et al. 1996). Y427 mediates the subsequent association with Grb2 (Salcini et al. 1994).

Numbering here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references used 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-452102 (Reactome) Phosphorylated STAT5A and STAT5B form homodimers and heterodimers in the cytosol (Gaffen et al. 1996, Rosenthal et al. 1997, also inferred from mouse homologs). Phosphorylation of a critical tyrosine residue in the SH domain (Y694 in STAT5A and Y699 in STAT5B) and intramolecular interactions between hydrophobic residues in the SH domain are required for dimerization (inferred from mouse homologs).
R-HSA-452108 (Reactome) Mutation analysis has shown that Y338, Y392 and Y510 are involved in IL-2-induced STAT protein binding. Phospho-tyrosines 338, 392 and 510 can each promote STAT5 activation (Gaffen et al. 1996), though Y510 appears to be the primary site for STAT5 binding (Gesbert et al. 1998). STAT3 may also be recruited to phospho-tyrosines on IL2RB and studies have shown defective IL-2 responses in STAT3-/- T cells, thereby supporting a functional role for STAT3 downstream of IL-2 signaling (Akaishi et al. 1998).
R-HSA-452122 (Reactome) Following stimulation by IL2, the IL2R beta chain become phosphorylated on multiple tyrosine residues. These phosphotyrosine residues recruit position-specific signaling or adaptor proteins, leading to the activation of downstream signaling pathways. Although multiple kinases are involved in the phosphorylation of IL-2R beta, JAK1-dependent phosphorylation of tyrosines 338, 392 and 510 is known to be involved in STAT protein binding (Gaffen et al. 1996). Phospho-tyrosine 338 has also been shown to participate in recruitment and subsequent phosphorylation of the adaptor Shc (Friedmann et al. 1996). N.B. Numbering in the literature is based on the mature peptide, with the 26 residue signal peptide removed. Positions given in this reaction refer to the canonical Uniprot sequence, e.g. 338 is equivalent to 364 of the canonical sequence P14784.
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) Interleukin-7 (IL7)-activated Signal transducer and activator of transcription 5A or 5B (typically referred to as STAT5) is recruited rapidly to the promoters of IL7-regulated genes (Ye et al. 2001, Stanton & Brodeur 2005).
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-508282 (Reactome) Studies have shown that coexpression of Syk with catalytically active Jak1 results in Syk phosphorylation whereas coexpression of Syk with catalytically active Jak3 does not, suggesting that IL-2 driven phosphorylation of Syk is driven by Jak1 (Zhou et al. 2000).
R-HSA-508292 (Reactome) Syk binds to the serine-rich (aa 267 to 322) S region of IL2RB and becomes activated upon IL-2 stimulation (Minami et al. 1995).
Syk is shown here binding with the IL2:IL2RB trimer:p-JAK1:JAK3 complex but it may become associated at an earlier stage of receptor activation.
R-HSA-508451 (Reactome) The proline rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko, 2005). PYK2 tyrosine phosphorlation is known to occur downstream of IL-2 stimulation in human peripheral T lymphocytes. This phosphorylation can be prevented by blocking IL-2 mediated JAK activity. Although the function of Pyk2 within the IL-2 signaling pathways remains uncertain, a dominant negative mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation which suggests that Pyk2 does indeed influence IL-2 driven immune cell responses.
R-HSA-508513 (Reactome) The proline-rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko 2005).
Coimmunoprecipitation experiments have demonstrated a physical association of Jak3 and Pyk2. A dominant interfering mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation. Collectively, these results suggest that Pyk2 is a component of the Jak-mediated IL-2 signaling pathway, but a role has not been firmly established.
R-HSA-5340385 (Reactome) T-helper (Th) cell-mediated immunity is required to eliminate pathogens effectively but unrestrained Th activity can contribute to tissue damage in many inflammatory and autoimmune diseases. The T-cell immunoglobulin and mucin domain-containing protein (HAVCR2, TIM3) inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and allo-immune responses and promotes immunological tolerance when it binds to its ligand, galectin-9 (LGALS9). The HAVCR2:LGALS9 complex achieves this inhibition by inducing apoptosis of Th1 cells. The human event is inferred from experimental data from mouse studies (Sanchez-Fueyo et al. 2003, Zhu et al. 2005).
R-HSA-9005980 (Reactome) Interleukin-21 (IL21) is a pleiotropic cytokine with four alpha-helical bundles. It is produced primarily by natural killer T cells, T follicular helper cells and TH17 cells, with lower levels of production by numerous other populations of lymphohaematopoietic cells (Spolski & Leonard 2014). IL21 binds Interleukin-21 receptor (IL21R, NILR) and Cytokine receptor common subunit gamma (IL2RG, GammaC).
IL21R has significant homology with the class I cytokine receptors Interleukin-2 receptor subunit beta (IL2RB) and Interleukin-4 receptor subunit alpha (IL4R) and was predicted to similarly form a complex with IL2RG. IL21R dimers can weakly bind and signal in response to IL21 but IL21 generates a much stronger response when IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). IL21R can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but IL2RG is required for IL21 induced signaling (Asao et al. 2001). The heteromeric IL21 receptor complex can activate JAK1, JAK3, Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2017). This is a black-box event because the pre-association of IL21R with JAK1 is inferred from the constitutive association of JAKs with other interleukin receptor subunits such as IL2R.
R-HSA-9006844 (Reactome) Interleukin-21 receptor (IL21R, NILR) can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but little or no signaling occurs (Asao et al. 2001) unless IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). The heteromeric IL21 receptor complex can activate JAK1 and JAK3.

This is a black box event because the pre-association of IL21R with JAK1 and of IL2RG with JAK3 is inferred from the mechanism of IL2 signaling.
R-HSA-9006850 (Reactome) The IL21 heteromeric receptor complex can activate JAK1 and JAK3 in response to Interleukin-21 (IL21), leading to JAK tyrosine phosphorylation (Asao et al. 2001, Habib et al. 2002).

This is a black box event because the mechanism leading to JAK phosphorylation is not established for this receptor complex.
R-HSA-9006870 (Reactome) The IL21R:IL2RG complex can activate Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2016).
R-HSA-9006873 (Reactome) The IL21 receptor complex can activate Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2016).

This is a black-box event because STAT phosphorylation is assumed to involve STAT binding though this has not been demonstrated for this receptor complex. In addition the mechanism that brings about STAT binding to the receptor, which presumably involves receptor tyrosine phosphorylation, is unclear.
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-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-919404 (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).
SHC kinases in IL2 signalingmim-catalysisR-HSA-452100 (Reactome)
SHC1R-HSA-452091 (Reactome)
SHIP1,2R-HSA-913374 (Reactome)
STAT1,STAT3,STAT4,STAT5R-HSA-9006873 (Reactome)
STAT5A,STAT5BR-HSA-452108 (Reactome)
SYKR-HSA-508292 (Reactome)
p-STAT5 dimerArrowR-HSA-452102 (Reactome)
p-STAT5 dimerArrowR-HSA-507937 (Reactome)
p-STAT5 dimerR-HSA-507937 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-919404 (Reactome)
p-STAT5A, p-STAT5BR-HSA-452102 (Reactome)
p85-containing Class 1A PI3KsR-HSA-508247 (Reactome)
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