Interleukin-2 family signaling (Homo sapiens)

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4, 26, 38, 463518, 1936, 497, 1867, 188, 3745143915, 15, 482747, 4923, 3013, 21, 22332511, 153529, 393317, 223, 14, 3143, 45cytosolnucleoplasmInterleukin receptorcomplexes withactivatedShc:GRB2:p-GAB2p-Y-JAK1 PIK3R2 IL2 GAB2 p-Y364,Y418,Y536-IL2RB GRB2-1 p-Y-JAK1 SHC1 IL2RA Interleukin receptorcomplexes withactivatedSHC1:GRB2:SOS1GAB2 IL2 SOS1 IL2RB IL2:IL2Rtrimer:p-JAK1:JAK3:SYKIL2RG HAVCR2PTK2BIL2:IL2RAp-Y699-STAT5B Interleukin receptorcomplexes withactivated SHC1IL2 ADPJAK3 JAK3 IL2RA p-Y-PTK2B IL2RA p-Y364,Y418,Y536-IL2RB IL2RG SHC1p-Y-SHC1 p-Y-SHC1 PIK3R3 INPP5D p-Y-SHC1 p-Y-JAK1 INPPL1 JAK3 p-Y-JAK1 IL2 STAT5IL2RG p-Y699-STAT5B IL2 JAK3 IL2:IL2Rtrimerp-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHCJAK3 p-Y694-STAT5A STAT5B SHC kinases in IL2signalingATPp-Y694-STAT5A IL2 p-Y364,Y418,Y536-IL2RB p-Y364,Y418,Y536-IL2RB IL2 IL2 IL2RA p-Y364,Y418,Y536-IL2RB PIK3R1 p-STAT5JAK1 PTPN6 IL2RA ADPIL2RG IL2 JAK3 IL2:IL2R trimerp-(Y338,392,510)betasubunit:p-JAK1:JAK3IL2RG GRB2-1 STAT5A p-Y364,Y418,Y536-IL2RB IL2 IL2RA JAK3:PYK2InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3Ksp-Y-JAK1 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 Interleukin receptorcompexes withactivatedShc:GRB2:GAB2GRB2-1:SOS1p-Y-JAK1 GRB2-1IL2RA p-Y-SYK High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 PIK3CD IL2:IL2Rtrimerp-(Y338,Y392,Y510)betasubunit:p-JAK1:JAK3:p-STAT5p-Y-SHC1 PIK3CB p-Y-JAK1 IL2RB IL2RB IL2:IL2RA:IL2RB:JAK1HAVCR2:LGALS9p-Y-GAB2 JAK3 IL2:IL2Rtrimer:p-JAK1:JAK3:p-SYKInterleukin receptorcomplexes withactivatedSHC1:SHIP1JAK3:p-PYK2JAK1 GRB2-1 IL2:IL2Rtrimer:p-JAK1:JAK3ATPPIK3CD IL2RA IL2 GRB2:GAB2IL2RG IL2RG Interleukin receptorcomplexes withactivatedSHC1:SHIP1,2IL2RG IL2RB ATPp-Y-JAK1 PIK3R2 p-Y-JAK1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 JAK3 IL2RA JAK3 p-Y364,Y418,Y536-IL2RB IL2RG High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 JAK3 GRB2-1 SYKp-Y364,Y418,Y536-IL2RB High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 p-STAT5 dimerATPIL2RA JAK3 JAK3 p-Y-JAK1 IL2RG JAK3 STAT5B GRB2-1 GRB2-1 IL2:IL2Rtrimer:JAK1:JAK3p-Y699-STAT5B LGALS9 IL2 p-Y-SHC1 PIK3CB IL2RG IL2RG p-Y364,Y418,Y536-IL2RB p-Y-SHC1 Interleukin receptorcomplexes withactivatedSHC1:SHIP:GRB2p-Y-SHC1 STAT5A p-Y-GAB2 PIK3R3 IL2RG PIK3R1 IL2RG p-Y694-STAT5A IL2RB:JAK1IL2 ADPIL2RA IL2RG p-Y-SHC1 ADPPTK2B p-Y694-STAT5A JAK1 p85-containing Class1A PI3KsIL2:IL2Rtrimerp-(Y338,392,510)betasubunit:p-JAK1:JAK3:STAT5RAF/MAP kinasecascadeIL2RB IL2RG IL2 p-Y-JAK1 p-Y-JAK1 IL2RAp-Y364,Y418,Y536-IL2RB SOS1 IL2RA IL2RG:JAK3IL2 p-Y364,Y418,Y536-IL2RB SYK IL2RA IL2p-Y-JAK1 PIK3CA IL2RB SHIP1,2IL2RA IL2RA LGALS9p-Y699-STAT5B JAK3 p-Y-SHC1 INPP5D IL2RGJAK3JAK3 JAK3 JAK3 IL2RA p-Y-JAK1 ATPIL2 p-Y364,Y418,Y536-IL2RB IL2 p-STAT5 dimerJAK3 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL2 ADPIL2RBIL2RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 HAVCR2 IL2RA IL2:IL2Rtrimerp-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHCLCK IL2RA IL2RG GRB2-1 INPPL1 PTPN6 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 IL2 JAK3 p-Y-JAK1 PIK3CA IL2RG JAK3 p-Y-JAK1 p-Y364,Y418,Y536-IL2RB p-Y-JAK1 JAK12, 9, 10, 12, 16...


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.

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Bibliography

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  1. Zhu MH, Berry JA, Russell SM, Leonard WJ.; ''Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.''; PubMed Europe PMC Scholia
  2. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA.; ''Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.''; PubMed Europe PMC Scholia
  3. Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T.; ''IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.''; PubMed Europe PMC Scholia
  4. Zhou YJ, Magnuson KS, Cheng TP, Gadina M, Frucht DM, Galon J, Candotti F, Geahlen RL, Changelian PS, O'Shea JJ.; ''Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation.''; PubMed Europe PMC Scholia
  5. Evans GA, Goldsmith MA, Johnston JA, Xu W, Weiler SR, Erwin R, Howard OM, Abraham RT, O'Shea JJ, Greene WC.; ''Analysis of interleukin-2-dependent signal transduction through the Shc/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require Shc phosphorylation or receptor association.''; PubMed Europe PMC Scholia
  6. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  7. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  8. Chi F, Chen L, Wang C, Li L, Sun X, Xu Y, Ma T, Liu K, Ma X, Shu X.; ''JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma.''; PubMed Europe PMC Scholia
  9. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O'Shea JJ, Borie DC.; ''Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.''; PubMed Europe PMC Scholia
  10. Sim GC, Radvanyi L.; ''The IL-2 cytokine family in cancer immunotherapy.''; PubMed Europe PMC Scholia
  11. Vallières F, Girard D.; ''Mechanism involved in interleukin-21-induced phagocytosis in human monocytes and macrophages.''; PubMed Europe PMC Scholia
  12. Ravichandran KS, Burakoff SJ.; ''The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation.''; PubMed Europe PMC Scholia
  13. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  14. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  15. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMed Europe PMC Scholia
  16. Dhillon S.; ''Tofacitinib: A Review in Rheumatoid Arthritis.''; PubMed Europe PMC Scholia
  17. Lin JX, Mietz J, Modi WS, John S, Leonard WJ.; ''Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells.''; PubMed Europe PMC Scholia
  18. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC Scholia
  19. Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S.; ''IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response.''; PubMed Europe PMC Scholia
  20. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  21. Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG.; ''Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins.''; PubMed Europe PMC Scholia
  22. Harkiolaki M, Tsirka T, Lewitzky M, Simister PC, Joshi D, Bird LE, Jones EY, O'Reilly N, Feller SM.; ''Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.''; PubMed Europe PMC Scholia
  23. Friedmann MC, Migone TS, Russell SM, Leonard WJ.; ''Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation.''; PubMed Europe PMC Scholia
  24. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  25. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC Scholia
  26. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  27. Winthrop KL.; ''The emerging safety profile of JAK inhibitors in rheumatic disease.''; PubMed Europe PMC Scholia
  28. Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC.; ''Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its alpha, beta, and gamma(c) receptors.''; PubMed Europe PMC Scholia
  29. Habib T, Senadheera S, Weinberg K, Kaushansky K.; ''The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3.''; PubMed Europe PMC Scholia
  30. Li H, Rostami A.; ''IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity.''; PubMed Europe PMC Scholia
  31. Behrmann I, Janzen C, Gerhartz C, Schmitz-Van de Leur H, Hermanns H, Heesel B, Graeve L, Horn F, Tavernier J, Heinrich PC.; ''A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation.''; PubMed Europe PMC Scholia
  32. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK.; ''The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.''; PubMed Europe PMC Scholia
  33. Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMed Europe PMC Scholia
  34. Sánchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutiérrez-Ramos JC, Coyle AJ, Strom TB.; ''Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.''; PubMed Europe PMC Scholia
  35. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  36. Miyazaki T, Takaoka A, Nogueira L, Dikic I, Fujii H, Tsujino S, Mitani Y, Maeda M, Schlessinger J, Taniguchi T.; ''Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway.''; PubMed Europe PMC Scholia
  37. Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC Scholia
  38. Neurath MF, Finotto S.; ''IL-9 signaling as key driver of chronic inflammation in mucosal immunity.''; PubMed Europe PMC Scholia
  39. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMed Europe PMC Scholia
  40. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ.; ''Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.''; PubMed Europe PMC Scholia
  41. Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS.; ''Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP.''; PubMed Europe PMC Scholia
  42. Minami Y, Nakagawa Y, Kawahara A, Miyazaki T, Sada K, Yamamura H, Taniguchi T.; ''Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway.''; PubMed Europe PMC Scholia
  43. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K.; ''Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex.''; PubMed Europe PMC Scholia
  44. Rochman Y, Spolski R, Leonard WJ.; ''New insights into the regulation of T cells by gamma(c) family cytokines.''; PubMed Europe PMC Scholia
  45. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  46. Nizsalóczki E, Csomós I, Nagy P, Fazekas Z, Goldman CK, Waldmann TA, Damjanovich S, Vámosi G, Mátyus L, Bodnár A.; ''Distinct spatial relationship of the interleukin-9 receptor with interleukin-2 receptor and major histocompatibility complex glycoproteins in human T lymphoma cells.''; PubMed Europe PMC Scholia
  47. Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C, Sun J, Whipple DA, Changelian PS.; ''Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.''; PubMed Europe PMC Scholia
  48. Naeger LK, McKinney J, Salvekar A, Hoey T.; ''Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling.''; PubMed Europe PMC Scholia
  49. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  50. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMed Europe PMC Scholia
  51. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T.; ''Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.''; PubMed Europe PMC Scholia
  52. Ravichandran KS, Igras V, Shoelson SE, Fesik SW, Burakoff SJ.; ''Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling.''; PubMed Europe PMC Scholia
  53. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  54. Gadina M, Sudarshan C, Visconti R, Zhou YJ, Gu H, Neel BG, O'Shea JJ.; ''The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines.''; PubMed Europe PMC Scholia
  55. Brockdorff JL, Gu H, Mustelin T, Kaltoft K, Geisler C, Röpke C, Ødum N.; ''Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a.''; PubMed Europe PMC Scholia
  56. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O.; ''Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID.''; PubMed Europe PMC Scholia
  57. Clark JD, Flanagan ME, Telliez JB.; ''Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.''; PubMed Europe PMC Scholia
  58. Harmer SL, DeFranco AL.; ''The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes.''; PubMed Europe PMC Scholia
  59. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  60. Nelson BH, Lord JD, Greenberg PD.; ''Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.''; PubMed Europe PMC Scholia
  61. Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM.; ''Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.''; PubMed Europe PMC Scholia
  62. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ.; ''Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain.''; PubMed Europe PMC Scholia
  63. Gu H, Pratt JC, Burakoff SJ, Neel BG.; ''Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation.''; PubMed Europe PMC Scholia
  64. Odai H, Sasaki K, Iwamatsu A, Nakamoto T, Ueno H, Yamagata T, Mitani K, Yazaki Y, Hirai H.; ''Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl.''; PubMed Europe PMC Scholia
  65. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  66. Landgraf BE, Goldstein B, Williams DP, Murphy JR, Sana TR, Smith KA, Ciardelli TL.; ''Recombinant interleukin-2 analogs. Dynamic probes for receptor structure.''; PubMed Europe PMC Scholia
  67. Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC.; ''Engagement of Gab1 and Gab2 in erythropoietin signaling.''; PubMed Europe PMC Scholia
  68. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG.; ''New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway.''; PubMed Europe PMC Scholia
  69. Ingham RJ, Okada H, Dang-Lawson M, Dinglasan J, van Der Geer P, Kurosaki T, Gold MR.; ''Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.''; PubMed Europe PMC Scholia
  70. Wang X, Lupardus P, Laporte SL, Garcia KC.; ''Structural biology of shared cytokine receptors.''; PubMed Europe PMC Scholia
  71. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115080view17:02, 25 January 2021ReactomeTeamReactome version 75
113522view12:00, 2 November 2020ReactomeTeamReactome version 74
112721view16:12, 9 October 2020ReactomeTeamReactome version 73
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

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NameTypeDatabase referenceComment
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)
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)
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)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STAT5ComplexR-HSA-452094 (Reactome)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
p-STAT5 dimerComplexR-HSA-507919 (Reactome)
p-STAT5 dimerComplexR-HSA-508012 (Reactome)
p-STAT5ComplexR-HSA-507929 (Reactome)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (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-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (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-912527 (Reactome)
ATPR-HSA-451942 (Reactome)
ATPR-HSA-452097 (Reactome)
ATPR-HSA-452100 (Reactome)
ATPR-HSA-452122 (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)
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)
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) 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).
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 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.
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) 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-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) 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-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-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)
STAT5R-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-STAT5ArrowR-HSA-919404 (Reactome)
p-STAT5R-HSA-452102 (Reactome)
p85-containing Class 1A PI3KsR-HSA-508247 (Reactome)
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