Interleukin-2 family signaling (Homo sapiens)
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Description
Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.
IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=451927
IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=451927
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| ADP | Metabolite | CHEBI:16761 (ChEBI)  | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| CSF2 [extracellular region] | Protein | P04141 (Uniprot-TrEMBL) | |
| CSF2RA [plasma membrane] | Protein | P15509 (Uniprot-TrEMBL) | |
| GAB2 [cytosol] | Protein | Q9UQC2 (Uniprot-TrEMBL) | |
| GDP [cytosol] | Metabolite | CHEBI:17552 (ChEBI) | |
| GDP | Metabolite | CHEBI:17552 (ChEBI) | |
| GRB2-1 [cytosol] | Protein | P62993-1 (Uniprot-TrEMBL) | |
| GRB2-1 | Protein | P62993-1 (Uniprot-TrEMBL) | |
| GRB2:GAB2 | Complex | REACT_24714 (Reactome) | |
| GRB2:SOS1 | Complex | REACT_4435 (Reactome) | |
| GTP [cytosol] | Metabolite | CHEBI:15996 (ChEBI) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| HRAS(1-186) [plasma membrane] | Protein | P01112 (Uniprot-TrEMBL) | |
| HRAS:GDP | Complex | REACT_24031 (Reactome) | |
| HRAS:GTP | Complex | REACT_24217 (Reactome) | |
| IL2 [extracellular region] | Protein | P60568 (Uniprot-TrEMBL) | |
| IL2:IL2R trimer:JAK1:JAK3 | Complex | REACT_27501 (Reactome) | |
| IL2:IL2R trimer:p-JAK1:JAK3:SYK | Complex | REACT_27852 (Reactome) | |
| IL2:IL2R trimer:p-JAK1:JAK3:p-SYK | Complex | REACT_27723 (Reactome) | |
| IL2:IL2R trimer:p-JAK1:JAK3 | Complex | REACT_27786 (Reactome) | |
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3:STAT5 | Complex | REACT_27906 (Reactome) | |
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3 | Complex | REACT_27939 (Reactome) | |
| IL2:IL2R trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC | Complex | REACT_27664 (Reactome) | |
| IL2:IL2R trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC | Complex | REACT_24532 (Reactome) | |
| IL2:IL2R trimer
p-(Y338,Y392, Y510) beta subunit:p-JAK1:JAK3:p-STAT5 | Complex | REACT_27707 (Reactome) | |
| IL2:IL2RA:IL2RB:JAK1 | Complex | REACT_27637 (Reactome) | |
| IL2:IL2RA | Complex | REACT_27750 (Reactome) | |
| IL2 | Protein | P60568 (Uniprot-TrEMBL) | |
| IL2RA [plasma membrane] | Protein | P01589 (Uniprot-TrEMBL) | |
| IL2RA | Protein | P01589 (Uniprot-TrEMBL) | |
| IL2RB [plasma membrane] | Protein | P14784 (Uniprot-TrEMBL) | |
| IL2RB:JAK1 | Complex | REACT_27842 (Reactome) | |
| IL2RB | Protein | P14784 (Uniprot-TrEMBL) | |
| IL2RG [plasma membrane] | Protein | P31785 (Uniprot-TrEMBL) | |
| IL2RG:JAK3 | Complex | REACT_24778 (Reactome) | |
| IL2RG | Protein | P31785 (Uniprot-TrEMBL) | |
| IL3 [extracellular region] | Protein | P08700 (Uniprot-TrEMBL) | |
| IL3RA [plasma membrane] | Protein | P26951 (Uniprot-TrEMBL) | |
| IL5 [extracellular region] | Protein | P05113 (Uniprot-TrEMBL) | |
| IL5RA [plasma membrane] | Protein | Q01344 (Uniprot-TrEMBL) | |
| INPP5D [cytosol] | Protein | Q92835 (Uniprot-TrEMBL) | |
| INPPL1 [cytosol] | Protein | O15357 (Uniprot-TrEMBL) | |
| Interleukin receptor
compexes with activated Shc:GRB2:GAB2 | REACT_24494 (Reactome) | ||
| Interleukin receptor
complexes with activated SHC1:GRB2:SOS1 | Complex | REACT_24582 (Reactome) | |
| Interleukin receptor
complexes with activated SHC1:SHIP1,2 | Complex | REACT_24093 (Reactome) | |
| Interleukin receptor
complexes with activated SHC1:SHIP:GRB2 | Complex | REACT_24297 (Reactome) | |
| Interleukin receptor
complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks | REACT_24797 (Reactome) | ||
| Interleukin receptor
complexes with activated Shc:GRB2:p-GAB2 | REACT_24779 (Reactome) | ||
| Interleukin receptor
complexes with activated SHC1:SHIP1 | Complex | REACT_24554 (Reactome) | |
| Interleukin receptor
complexes with activated SHC1 | REACT_24730 (Reactome) | ||
| JAK1 [cytosol] | Protein | P23458 (Uniprot-TrEMBL) | |
| JAK1 | Protein | P23458 (Uniprot-TrEMBL) | |
| JAK2 [cytosol] | Protein | O60674 (Uniprot-TrEMBL) | |
| JAK3 [cytosol] | Protein | P52333 (Uniprot-TrEMBL) | |
| JAK3:PYK2 | Complex | REACT_27865 (Reactome) | |
| JAK3:p-PYK2 | Complex | REACT_27631 (Reactome) | |
| JAK3 | Protein | P52333 (Uniprot-TrEMBL) | |
| PIK3CA [cytosol] | Protein | P42336 (Uniprot-TrEMBL) | |
| PIK3CB [cytosol] | Protein | P42338 (Uniprot-TrEMBL) | |
| PIK3CD [plasma membrane] | Protein | O00329 (Uniprot-TrEMBL) | |
| PTK2B [cytosol] | Protein | Q14289 (Uniprot-TrEMBL) | |
| PTK2B | Protein | Q14289 (Uniprot-TrEMBL) | |
| PTPN6 [cytosol] | Protein | P29350 (Uniprot-TrEMBL) | |
| RAF/MAP kinase cascade | Pathway | WP2735 (WikiPathways) | The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus. |
| SHC kinases in IL2 signaling | Protein | REACT_27386 (Reactome) | |
| SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| SHIP1,2 | REACT_24095 (Reactome) | ||
| SOS1 [cytosol] | Protein | Q07889 (Uniprot-TrEMBL) | |
| STAT5A [cytosol] | Protein | P42229 (Uniprot-TrEMBL) | |
| STAT5B [cytosol] | Protein | P51692 (Uniprot-TrEMBL) | |
| STAT5 | Protein | REACT_24211 (Reactome) | |
| SYK [cytosol] | Protein | P43405 (Uniprot-TrEMBL) | |
| SYK | Protein | P43405 (Uniprot-TrEMBL) | |
| p-STAT5 dimer | Complex | REACT_24109 (Reactome) | |
| p-STAT5 dimer | Complex | REACT_24289 (Reactome) | |
| p-STAT5A/B | Protein | REACT_24299 (Reactome) | |
| p-Y-JAK1 [cytosol] | Protein | P23458 (Uniprot-TrEMBL) | |
| p-Y-PTK2B [cytosol] | Protein | Q14289 (Uniprot-TrEMBL) | |
| p-Y-SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| p-Y-SYK [plasma membrane] | Protein | P43405 (Uniprot-TrEMBL) | |
| p-Y349,Y350,Y427-SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| p-Y364,Y418,Y536-IL2RB [plasma membrane] | Protein | P14784 (Uniprot-TrEMBL) | |
| p-Y593,Y628-CSF2RB [plasma membrane] | Protein | P32927 (Uniprot-TrEMBL) | |
| p-Y694-STAT5A [cytosol] | Protein | P42229 (Uniprot-TrEMBL) | |
| p-Y694-STAT5A [nucleoplasm] | Protein | P42229 (Uniprot-TrEMBL) | |
| p-Y699-STAT5B [cytosol] | Protein | P51692 (Uniprot-TrEMBL) | |
| p-Y699-STAT5B [nucleoplasm] | Protein | P51692 (Uniprot-TrEMBL) | |
| p85-containing Class 1A PI3Ks | Complex | REACT_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
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_23782 (Reactome) | ||
| ADP | Arrow | REACT_27150 (Reactome) | ||
| ADP | Arrow | REACT_27154 (Reactome) | ||
| ADP | Arrow | REACT_27196 (Reactome) | ||
| ADP | Arrow | REACT_27274 (Reactome) | ||
| ATP | REACT_23782 (Reactome) | |||
| ATP | REACT_27150 (Reactome) | |||
| ATP | REACT_27154 (Reactome) | |||
| ATP | REACT_27196 (Reactome) | |||
| ATP | REACT_27274 (Reactome) | |||
| GDP | Arrow | REACT_23928 (Reactome) | ||
| GRB2-1 | REACT_23911 (Reactome) | |||
| GRB2:GAB2 | REACT_23856 (Reactome) | |||
| GRB2:SOS1 | REACT_23828 (Reactome) | |||
| GTP | REACT_23928 (Reactome) | |||
| HRAS:GDP | REACT_23928 (Reactome) | |||
| HRAS:GTP | Arrow | REACT_23928 (Reactome) | ||
| IL2:IL2R trimer:JAK1:JAK3 | Arrow | REACT_27145 (Reactome) | ||
| IL2:IL2R trimer:JAK1:JAK3 | REACT_27274 (Reactome) | |||
| IL2:IL2R trimer:JAK1:JAK3 | mim-catalysis | REACT_27274 (Reactome) | ||
| IL2:IL2R trimer:p-JAK1:JAK3:SYK | Arrow | REACT_27313 (Reactome) | ||
| IL2:IL2R trimer:p-JAK1:JAK3:SYK | REACT_27233 (Reactome) | |||
| IL2:IL2R trimer:p-JAK1:JAK3:SYK | mim-catalysis | REACT_27233 (Reactome) | ||
| IL2:IL2R trimer:p-JAK1:JAK3:p-SYK | Arrow | REACT_27233 (Reactome) | ||
| IL2:IL2R trimer:p-JAK1:JAK3 | Arrow | REACT_27274 (Reactome) | ||
| IL2:IL2R trimer:p-JAK1:JAK3 | REACT_27196 (Reactome) | |||
| IL2:IL2R trimer:p-JAK1:JAK3 | REACT_27313 (Reactome) | |||
| IL2:IL2R trimer:p-JAK1:JAK3 | mim-catalysis | REACT_27196 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3:STAT5 | Arrow | REACT_27183 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3:STAT5 | REACT_27154 (Reactome) | |||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3:STAT5 | mim-catalysis | REACT_27154 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3 | Arrow | REACT_27196 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3 | Arrow | REACT_27314 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3 | REACT_27183 (Reactome) | |||
| IL2:IL2R trimer
p-(Y338,392,510) beta subunit:p-JAK1:JAK3 | REACT_27317 (Reactome) | |||
| IL2:IL2R trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC | Arrow | REACT_27317 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC | REACT_27150 (Reactome) | |||
| IL2:IL2R trimer
p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC | Arrow | REACT_27150 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,Y392, Y510) beta subunit:p-JAK1:JAK3:p-STAT5 | Arrow | REACT_27154 (Reactome) | ||
| IL2:IL2R trimer
p-(Y338,Y392, Y510) beta subunit:p-JAK1:JAK3:p-STAT5 | REACT_27314 (Reactome) | |||
| IL2:IL2RA:IL2RB:JAK1 | Arrow | REACT_27278 (Reactome) | ||
| IL2:IL2RA:IL2RB:JAK1 | REACT_27145 (Reactome) | |||
| IL2:IL2RA | Arrow | REACT_27273 (Reactome) | ||
| IL2:IL2RA | REACT_27278 (Reactome) | |||
| IL2RA | REACT_27273 (Reactome) | |||
| IL2RB:JAK1 | Arrow | REACT_27175 (Reactome) | ||
| IL2RB:JAK1 | REACT_27278 (Reactome) | |||
| IL2RB | REACT_27175 (Reactome) | |||
| IL2 | REACT_27273 (Reactome) | |||
| IL2RG:JAK3 | Arrow | REACT_27167 (Reactome) | ||
| IL2RG:JAK3 | REACT_27145 (Reactome) | |||
| IL2RG | REACT_27167 (Reactome) | |||
| Interleukin receptor
compexes with activated Shc:GRB2:GAB2 | Arrow | REACT_23856 (Reactome) | ||
| Interleukin receptor
compexes with activated Shc:GRB2:GAB2 | REACT_23782 (Reactome) | |||
| Interleukin receptor
complexes with activated SHC1:GRB2:SOS1 | Arrow | REACT_23828 (Reactome) | ||
| Interleukin receptor
complexes with activated SHC1:GRB2:SOS1 | mim-catalysis | REACT_23928 (Reactome) | ||
| Interleukin receptor
complexes with activated SHC1:SHIP1,2 | Arrow | REACT_23874 (Reactome) | ||
| Interleukin receptor
complexes with activated SHC1:SHIP:GRB2 | Arrow | REACT_23911 (Reactome) | ||
| Interleukin receptor
complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks | Arrow | REACT_24024 (Reactome) | ||
| Interleukin receptor
complexes with activated Shc:GRB2:p-GAB2 | Arrow | REACT_23782 (Reactome) | ||
| Interleukin receptor
complexes with activated Shc:GRB2:p-GAB2 | REACT_24024 (Reactome) | |||
| Interleukin receptor
complexes with activated SHC1:SHIP1 | REACT_23911 (Reactome) | |||
| Interleukin receptor
complexes with activated SHC1 | REACT_23828 (Reactome) | |||
| Interleukin receptor
complexes with activated SHC1 | REACT_23856 (Reactome) | |||
| Interleukin receptor
complexes with activated SHC1 | REACT_23874 (Reactome) | |||
| JAK1 | REACT_27175 (Reactome) | |||
| JAK3:PYK2 | Arrow | REACT_27192 (Reactome) | ||
| JAK3:PYK2 | REACT_27136 (Reactome) | |||
| JAK3:p-PYK2 | Arrow | REACT_27136 (Reactome) | ||
| JAK3 | REACT_27167 (Reactome) | |||
| JAK3 | REACT_27192 (Reactome) | |||
| PTK2B | REACT_27192 (Reactome) | |||
| REACT_23774 (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). | |||
| REACT_23782 (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). | |||
| REACT_23827 (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 funcions, 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). | |||
| REACT_23828 (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. | |||
| REACT_23856 (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). | |||
| REACT_23874 (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). | |||
| REACT_23911 (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). | |||
| REACT_23928 (Reactome) | Recruitment of Sos1 to the receptor complex brings it into contact with membrane-associated Ras-GDP. Interactions with Ras modulate Sos1 activity in a two-step manner (McKay & Morrison, 2007). Sos1 acts as a guanine exchange factor for Ras (Chardin et al. 1993), activating the Ras-Raf-MAPK pathway. | |||
| REACT_24024 (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. | |||
| REACT_27136 (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. | |||
| REACT_27145 (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. | |||
| REACT_27150 (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. | |||
| REACT_27154 (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 phophorylated in lymphocytes activated by IL-2 but the funtion of this is unclear (Xue et al. 2002). | |||
| REACT_27167 (Reactome) | IL-2 receptor gamma chain (IL2RG) associates with Janus Kinase 3 (JAK3). The carboxyl terminal region of IL2RG has been shown to be important for this asociation (Miyazaki et al. 1994, Zhu et al. 1998). | |||
| REACT_27175 (Reactome) | Janus Kinase 1 (JAK1) constitutively associates with IL-2R beta. | |||
| REACT_27183 (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). | |||
| REACT_27192 (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. | |||
| REACT_27196 (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. | |||
| REACT_27233 (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). | |||
| REACT_27273 (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. | |||
| REACT_27274 (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 IL-2 receptor, leading to severe immunodeficiency due to a lack of IL2R 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. | |||
| REACT_27278 (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. | |||
| REACT_27313 (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. | |||
| REACT_27314 (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). | |||
| REACT_27317 (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. | |||
| SHC kinases in IL2 signaling | mim-catalysis | REACT_27150 (Reactome) | ||
| SHC1 | REACT_27317 (Reactome) | |||
| SHIP1,2 | REACT_23874 (Reactome) | |||
| STAT5 | REACT_27183 (Reactome) | |||
| SYK | REACT_27313 (Reactome) | |||
| p-STAT5 dimer | Arrow | REACT_23774 (Reactome) | ||
| p-STAT5 dimer | Arrow | REACT_23827 (Reactome) | ||
| p-STAT5 dimer | REACT_23774 (Reactome) | |||
| p-STAT5A/B | Arrow | REACT_27314 (Reactome) | ||
| p-STAT5A/B | REACT_23827 (Reactome) | |||
| p85-containing Class 1A PI3Ks | REACT_24024 (Reactome) |
