Abstract
Interleukin-2 is one of the critical cytokines that control the proliferation and differentiation of cells of the immune system. The present article briefly reviews the current and recently established knowledge on the intracellular signaling events that convert the initial interaction of IL-2 with its receptor into pathways leading to the various biological functions. A first step in IL-2 signaling is the activation of several protein tyrosine kinases that phosphorylate a large array of intracellular substrates including the receptor complex. Phosphorylated tyrosine residues within the receptor then serve as docking sites for multimolecular signaling complexes that initiate three major pathways: the Jak-STAT pathway controlling gene transcription, the Ras-MAPK pathway leading to cell proliferation and gene transcription as well, and the PI3-kinase pathway involved in antiapoptotic signaling and organization of the cytoskeleton. Finally, other recently identified and presumably important tyrosine kinase substrates, whose significance is not yet fully understood, are described.
Similar content being viewed by others
REFERENCES
Morgan DA, Ruscetti FW, Gallo R: Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193:1007–1008, 1976
Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J: Structure and expression of a cloned cDNA for human interleukin-2. Nature 302:305–310, 1983
Lenardo MJ: Fas and the art of lymphocyte maintenance. J Exp Med 183:721–724, 1996
Piazza C, Gilardini Montani MS, Moretti S, Cundari E, Piccolella E: CD4+ T cells kill CD8+ T cells via Fas/Fas ligand-mediated apoptosis. J Immunol 158:1503–1506, 1997
Smith KA: Interleukin-2: inception, impact, and implications. Science 240:1169–1176, 1988
Bazan JF: Haemopoietic receptors and helical cytokines. Immunol Today 11:350–354, 1990
Theze J: Cytokine receptors: a combinative family of molecules. Eur Cytokine Netw 5:353–368, 1994
Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T: Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA 88:11349–11353, 1991
Goldsmith MA, Xu W, Amaral MC, Kuczek ES, Greene WC: The cytoplasmic domain of the interleukin-2 receptor β chain contains both unique and functionally redundant signal transduction elements. J Biol Chem 269:14698–14704, 1994
Goldsmith MA, Lai SY, Xu W, Amaral MC, Kuczek ES, Parent LJ, Mills GB, Tarr KL, Longmore GD, Greene WC: Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γ c chain. J Biol Chem 270:21729–21737, 1995
Miyazaki T, Liu ZJ, Kawahara A, Minami Y, Yamada K, Tsujimoto Y, Barsoumian EL, Permutter RM, Taniguchi T: Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell 81:223–231, 1995
Saltzman EM, Thom RR, Casnellie JE: Activation of a tyrosine protein kinase is an early event in the stimulation of T lymphocytes by interleukin-2. J Biol Chem 263:6956–6959, 1988
Nakamura Y, Russell SM, Mess SA, Friedmann M, Erdos M, Francois C, Jacques Y, Adelstein S, Leonard WJ: Heterodimerization of the IL-2 receptor β-and γ-chain cytoplasmic domains is required for signalling. Nature 369:330–333, 1994
Nelson BH, Lord JD, Greenberg PD: Cytoplasmic domains of the interleukin-2 receptor β and γ chains mediate the signal for T-cell proliferation. Nature 369:333–336, 1994
Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD, Perlmutter RM, Taniguchi T: Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science 252:1523–1528, 1991
Minami Y, Kono T, Yamada K, Kobayashi N, Kawahara A, Perlmutter RM, Taniguchi T: Association of p56lck with IL-2 receptor β chain is critical for the IL-2-induced activation of p56lck. EMBO J 12:759–768, 1993
Kobayashi N, Kono T, Hatakeyama M, Minami Y, Miyazaki T, Perlmutter RM, Taniguchi T: Functional coupling of the srcfamily protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: Implications for redundancy and pleiotropism in cytokine signal transduction. Proc Natl Acad Sci USA 90:4201–4205, 1993
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. Immunity 2:89–100, 1995
Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN, et al.: Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 266:1045–1047, 1994
Velazquez L, Fellous M, Stark GR, Pellegrini S: A protein tyrosine kinase in the interferon α/β signaling pathway. Cell 70:313–322, 1992
Muller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silvennoinen O, Harpur AG, Barbieri G, Witthuhn BA, Schindler C, et al.: The protein tyrosine kinase JAK1 complements defects in interferon-α/β and-γ signal transduction. Nature 366:129–135, 1993
Zhang Q, Nowak I, Vonderheid EC, Rook AH, Kadin ME, Nowell PC, Shaw LM, Wasik MA: Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. Proc Natl Acad Sci USA 93:9148–9153, 1996
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM: Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645–648, 1996
Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, et al.: Mutation of Jak3 in a patient with SCID: essential role of JAK3 in lymphoid development. Science 270:797–800, 1995
Kawahara A, Minami Y, Miyazaki T, Ihle JN, Taniguchi T: Critical role of the interleukin 2 (IL-2) receptor γ-chain associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction. Proc Natl Acad Sci USA 92:8724–8728, 1995
Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP, Doherty PC, Grosveld GC, Ihle JN: Defective lymphoid development in mice lacking Jak3. Science 270:800–802, 1995
Zhao Y, Wagner F, Frank SJ, Kraft AS: The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte-macrophage colony-stimulating factor receptor β c chain. J Biol Chem 270:13814–13818, 1995
Chen M, Cheng A, Chen YQ, Hymel A, Hanson EP, Kimmel L, Minami Y, Taniguchi T, Changelian PS, JJ OS: The amino terminus of JAK3 is necessary and sufficient for binding to the common γ chain and confers the ability to transmit interleukin 2-mediated signals. Proc Natl Acad Sci USA 94:6910–6915, 1997
Higuchi M, Asao H, Tanaka N, Oda K, Takeshita T, Nakamura M, Van Snick J, Sugamura K: Dispensability of Jak1 tyrosine kinase for interleukin-2-induced cell growth signaling in a human T cell line. Eur J Immunol 26:1322–1327, 1996
Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A, et al.: Profound block in thymocyte development in mice lacking p561ck. Nature 357:161–164, 1992
Horak ID, Gress RE, Lucas PJ, Horak EM, Waldmann TA, Bolen JB: T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p561ck. Proc Natl Acad Sci USA 88:1996–2000, 1991
Ellis C, Moran M, McCormick F, Pawson T: Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature 343:377–381, 1990
Amrein KE, Flint N, Panholzer B, Burn P: Ras GTPase-activating protein: A substrate and a potential binding protein of the protein-tyrosine kinase p561ck. Proc Natl Acad Sci USA 89:3343–3346, 1992
Vogel LB, Fujita DJ: p70 phosphorylation and binding to p561ck is an early event in interleukin-2-induced onset of cell cycle progression in T-lymphocytes. J Biol Chem 270:2506–2511, 1995
Karnitz L, Sutor SL, Torigoe T, Reed JC, Bell MP, McKean DJ, Leibson PJ, Abraham RT: Effects of p561ck deficiency on the growth and cytolytic effector function of an interleukin-2-dependent cytotoxic T-cell line. Mol Cell Biol 12:4521–4530, 1992
Mills GB, Arima N, May C, Hill M, Schmandt R, Li J, Miyamoto NG, Greene WC: Neither the LCK nor the FYN kinases are obligatory for IL-2-mediated signal transduction in HTLV-I-infected human T cells. Int Immunol 4:1233–1243, 1992
Weiss A, Littman DR: Signal transduction by lymphocyte antigen receptors. Cell 76:263–274, 1994
Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A: Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product. Immunity 5:591–604, 1996
Evans GA, Howard OM, Erwin R, Farrar WL: Interleukin-2 induces tyrosine phosphorylation of the vav proto-oncogene product in human T cells: Lack of requirement for the tyrosine kinase lck. Biochem J 294:339–342, 1993
Asao H, Takeshita T, Nakamura M, Nagata K, Sugamura K: Interleukin 2 (IL-2)-induced tyrosine phosphorylation of IL-2 receptor p75. J Exp Med 171:637–644, 1990
Asao H, Kumaki S, Takeshita T, Nakamura M, Sugamura K: IL-2-dependent in vivo and in vitro tyrosine phosphorylation of IL-2 receptor γ chain. FEBS Lett 304:141–145, 1992
Friedmann MC, Migone TS, Russell SM, Leonard WJ: Different interleukin 2 receptor β-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc Natl Acad Sci USA 93:2077–2082, 1996
Oakes SA, Candotti F, Johnston JA, Chen YQ, Ryan JJ, Taylor N, Liu X, Hennighausen L, Notarangelo LD, Paul WE, Blaese RM, O'Shea JJ: Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways. Immunity 5:605–615, 1996
Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA: Distinct tyrosine residues within the interleukin-2 receptor β chain drive signal transduction specificity, redundancy, and diversity. J Biol Chem 271:21381–21390, 1996
Fujii H, Nakagawa Y, Schindler U, Kawahara A, Mori H, Gouilleux F, Groner B, Ihle JN, Minami Y, Miyazaki T, et al.: Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor β chain but is not essential for the proliferative signal transmission. Proc Natl Acad Sci USA 92:5482–5486, 1995
Darnell JE Jr, Kerr IM, Stark GR: Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421, 1994
Gilmour KC, Pine R, Reich NC: Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes. Proc Natl Acad Sci USA 92:10772–10776, 1995
Frank DA, Robertson MJ, Bonni A, Ritz J, Greenberg ME: Interleukin 2 signaling involves the phosphorylation of Stat proteins. Proc Natl Acad Sci USA 92:7779–7783, 1995
Nielsen M, Svejgaard A, Skov S, Odum N: Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes. Eur J Immunol 24:3082–3086, 1994
Beadling C, Ng J, Babbage JW, Cantrell DA: Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J 15:1902–1913, 1996
Wen Z, Zhong Z, Darnell JE Jr: Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250, 1995
Kirken RA, Malabarba MG, Xu J, DaSilva L, Erwin RA, Liu X, Hennighausen L, Rui H, Farrar WL: Two discrete regions of interleukin-2 (IL2) receptor β independently mediate IL2 activation of a PD98059/rapamycin/wortmannin-insensitive Stat5a/b serine kinase. J Biol Chem 272:15459–15465, 1997
Wang D, Stravopodis D, Teglund S, Kitazawa J, Ihle JN: Naturally occurring dominant negative variants of Stat5. Mol Cell Biol 16:6141–6148, 1996
Nakajima H, Liu XW, Wynshaw-Boris A, Rosenthal LA, Imada K, Finbloom DS, Hennighausen L, Leonard WJ: An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor α chain induction. Immunity 7:691–701, 1997
John S, Robbins CM, Leonard WJ: An IL-2 response element in the human IL-2 receptor α chain promoter is a composite element that binds Stat5, Elf-1, HMG-I(Y) and a GATA family protein. EMBO J 15:5627–5635, 1996
Lecine P, Algarte M, Rameil P, Beadling C, Bucher P, Naholz M, Imbert J: Elf-1 and Stat5 bind to a critical element in a new enhancer of the human interleukin-2 receptor α gene. Mol Cell Biol 16:6829–6840, 1996
Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A: Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: Role of Stat5 in proliferation. EMBO J 15:2425–2433, 1996
Dautry F, Weil D, Yu J, Dautry-Varsat A: Regulation of pim and myb mRNA accumulation by interleukin 2 and interleukin 3 in murine hematopoietic cell lines. J Biol Chem 263:17615–17620, 1988
Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A: A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 14:2816–2826, 1995
Feldman GM, Rosenthal LA, Liu X, Hayes MP, Wynshaw-Boris A, Leonard WJ, Hennighausen L, Finbloom DS: STAT5A-deficient mice demonstrate a defect in granulocyte-macrophage colony-stimulating factor-induced proliferation and gene expression. Blood 90:1768–1776, 1997
Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A, Yoshimura A: CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89:3148–3154, 1997
Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A: A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921–924, 1997
Aman MJ, Leonard WJ: Cytokine-inducible signaling inhibitors. Curr Biol 7:784–788, 1997
Bos JL: ras oncogenes in human cancer: A review. Cancer Res 49:4682–4689, 1989
Sakai N, Ogiso Y, Fujita H, Watari H, Koike T, Kuzumaki N: Induction of apoptosis by a dominant negative H-RAS mutant (116Y) in K562 cells. Exp Cell Res 215:131–136, 1994
Kinoshita T, Yokota T, Arai K, Miyajima A: Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. Oncogene 10:2207–2212, 1995
Chen CY, Faller DV: Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. Oncogene 11:1487–1498, 1995
Graves JD, Downward J, Izquierdo-Pastor M, Rayter S, Warne PH, Cantrell DA: The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J Immunol 148:2417–2422, 1992
Satoh T, Nakafuku M, Kaziro Y: Function of Ras as a molecular switch in signal transduction. J Biol Chem 267:24149–24152, 1992
Zhu X, Suen KL, Barbacid M, Bolen JB, Fargnoli J: Interleukin-2-induced tyrosine phosphorylation of She proteins correlates with factor-dependent T cell proliferation. J Biol Chem 269:5518–5522, 1994
Ravichandran KS, Burakoff SJ: The adapter protein She interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem 269:1599–1602, 1994
Evans GA, Goldsmith MA, Johnston JA, Xu W, Weiler SR, Erwin R, Howard OM, Abraham RT, JJ OS, Greene WC, et al.: Analysis of interleukin-2-dependent signal transduction through the She/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require She phosphorylation or receptor association. J Biol Chem 270:28858–28863, 1995
Satoh T, Minami Y, Kono T, Yamada K, Kawahara A, Taniguchi T, Kaziro Y: Interleukin 2-induced activation of Ras requires two domains of interleukin 2 receptor β subunit, the essential region for growth stimulation and Lck-binding domain. J Biol Chem 267:25423–25427, 1992
Perkins GR, Marvel J, Collins MK: Interleukin 2 activates extracellular signal-regulated protein kinase 2. J Exp Med 178:1429–1434, 1993
de Vries-Smits AM, Burgering BM, Leevers SJ, Marshall CJ, Bos JL: Involvement of p21ras in activation of extracellular signal-regulated kinase 2. Nature 357:602–604, 1992
Crawley JB, Rawlinson L, Lali FV, Page TH, Saklatvala J, Foxwell BM: T cell proliferation in response to interleukins 2 and 7 requires p38MAP kinase activation. J Biol Chem 272:15023–15027, 1997
Smeal T, Binetruy B, Mercola DA, Birrer M, Karin M: Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354:494–496, 1991
Binetruy B, Smeal T, Karin M: Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature 351:122–127, 1991
Kapeller R, Cantley LC: Phosphatidylinositol 3-kinase. Bioessays 16:565–576, 1994
Inukai K, Funaki M, Ogihara T, Katagiri H, Kanda A, Anai M, Fukushima Y, Hosaka T, Suzuki M, Shin BC, Takata K, Yazaki Y, Kikuchi M, Oka Y, Asano T: p85α gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase (Pi 3-kinase), p50α, p55α, and p85α, with different Pi 3-kinase activity elevating responses to insulin. J Biol Chem 272:7873–7882, 1997
Antonetti DA, Algenstaedt P, Kahn CR: Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol Cell Biol 16:2195–2203, 1996
Pons S, Asano T, Glasheen E, Miralpeix M, Zhang Y, Fisher TL, Myers MG Jr, Sun XJ, White MF: The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase. Mol Cell Biol 15:4453–4465, 1995
Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD: Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 β protein by using the baculovirus expression system. Biochem J 288:395–405, 1992
Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al.: SH2 domains recognize specific phosphopeptide sequences. Cell 72:767–778, 1993
Augustine JA, Sutor SL, Abraham RT: Interleukin 2-and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes. Mol Cell Biol 11:4431–4440, 1991
Merida I, Diez E, Gaulton GN: IL-2 binding activates a tyrosine-phosphorylated phosphatidylinositol-3-kinase. J Immunol 147:2202–2207, 1991
Reif K, Nobes CD, Thomas G, Hall A, Cantrell DA: Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways. Curr Biol 6:1445–1455, 1996
Vogel LB, Fujita DJ: The SH3 domain of p561ck is involved in binding to phosphatidylinositol 3′-kinase from T lymphocytes. Mol Cell Biol 13:7408–7417, 1993
Taichman R, Merida I, Torigoe T, Gaulton GN, Reed JC: Evidence that protein tyrosine kinase p56-Lck regulates the activity of phosphatidylinositol-3′-kinase in interleukin-2-dependent T-cells. J Biol Chem 268:20031–20036, 1993
Kanazawa T, Keeler ML, Varticovski L: Serine-rich region of the IL-2 receptor β-chain is required for activation of phosphatidylinositol 3-kinase. Cell Immunol 156:378–388, 1994
Truitt KE, Mills GB, Turck CW, Imboden JB: SH2-dependent association of phosphatidylinositol 3′-kinase 85-kDa regulatory subunit with the interleukin-2 receptor β chain. J Biol Chem 269:5937–5943, 1994
Monfar M, Lemon KP, Grammer TC, Cheatham L, Chung J, Vlahos CJ, Blenis J: Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol Cell Biol 15:326–337, 1995
Reif K, Burgering BM, Cantrell DA: Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J Biol Chem 272:14426–14433, 1997
Ahmed NN, Grimes HL, Bellacosa A, Chan TO, Tsichlis PN: Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci USA 94:3627–3632, 1997
Gonzalez-Garcia A, Merida I, Martinez AC, Carrera AC: Intermediate affinity interleukin-2 receptor mediates survival via a phosphatidylinositol 3-kinase-dependent pathway. J Biol Chem 272:10220–10226, 1997
Gomez J, Martinez C, Garcia A, Rebollo A: Association of phosphatidylinositol 3 kinase to protein kinase C zeta during interleukin-2 stimulation. Eur J Immunol 26:1781–1787, 1996
Gomez J, Garcia A, L R-B, Bonay P, Martinez AC, Silva A, Fresno M, Carrera AC, Eicher-Streiber C, Rebollo A: IL-2 signaling controls actin organization through Rho-like protein family, phosphatidylinositol 3-kinase, and protein kinase C-zeta. J Immunol 158:1516–1522, 1997
Neel BG: Role of phosphatases in lymphocyte activation. Curr Opin Immunol 9:405–420, 1997
Frearson JA, Alexander DR: The role of phosphotyrosine phosphatases in haematopoietic cell signal transduction. Bioessays 19:417–427, 1997
Pingel JT, Thomas ML: Evidence that the leukocyte-common antigen is required for antigen-induced T lymphocyte proliferation. Cell 58:1055–1065, 1989
Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, MattHews RJ, Thomas ML, Beier DR: Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73:1445–1454, 1993
Milarski KL, Saltiel AR: Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem 269:21239–21243, 1994
Bennett AM, Hausdorff SF, AM OR, Freeman RM, Neel BG: Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol Cell Biol 16:1189–1202, 1996
Adachi M, Ishino M, Torigoe T, Minami Y, Matozaki T, Miyazaki T, Taniguchi T, Hinoda Y, Imai K: Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor β chain. Oncogene 14:1629–1633, 1997
Nelson BH, McIntosh BC, Rosencrans LL, Greenberg PD: Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor γ(c) chain for Janus kinase activation leading to T cell proliferation. Proc Natl Acad Sci USA 94:1878–1883, 1997
Tauchi T, Feng GS, Shen R, Hoatlin M, Bagby GC Jr, Kabat D, Lu L, Broxmeyer HE: Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem 270:5631–5635, 1995
Adachi M, Torigoe T, Sekiya M, Minami Y, Taniguchi T, Hinoda Y, Yachi A, Reed JC, Imai K: IL-2-induced gene expression of protein-tyrosine phosphatase LC-PTP requires acidic and serinerich regions within IL-2 receptor β chain. FEBS Lett 372:113–118, 1995
Takeshita T, Arita T, Higuchi M, Asao H, Endo K, Kuroda H, Tanaka N, Murata K, Ishii N, Sugamura K: STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction. Immunity 6:449–457, 1997
Gesbert F, Garbay C, Bertoglio J: Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells. J Biol Chem 273:3986–3993, 1998
Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HCd: v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas. Proc Natl Acad Sci USA 86:1168–1172, 1989
Blake TJ, Shapiro M, Morse HCd, Langdon WY: The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif. Oncogene 6:653–657, 1991
Mayer BJ, Hamaguchi M, Hanafusa H: A novel viral oncogene with structural similarity to phospholipase C. Nature 332:272–275, 1988
Matsuda M, Tanaka S, Nagata S, Kojima A, Kurata T, Shibuya M: Two species of human CRK cDNA encode proteins with distinct biological activities. Mol Cell Biol 12:3482–3489, 1992
ten Hoeve J, Morris C, Heisterkamp N, Groffen J: Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 8:2469–2474, 1993
ten Hoeve J, Kaartinen V, Fioretos T, Haataja L, Voncken JW, Heisterkamp N, Groffen J: Cellular interactions of CRKL, and SH2-SH3 adaptor protein. Cancer Res 54:2563–2567, 1994
Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD: Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL). J Biol Chem 272:10248–10253, 1997
Reedquist KA, Fukazawa T, Panchamoorthy G, Langdon WY, Shoelson SE, Druker BJ, Band H: Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G. J Biol Chem 271:8435–8442, 1996
Sattler M, Salgia R, Shrikhande G, Verma S, Uemura N, Law SF, Golemis EA, Griffin JD: Differential signaling after β1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1). J Biol Chem 272:14320–14326, 1997
Ota Y, Samelson LE: The product of the proto-oncogene c-cbl: A negative regulator of the Syk tyrosine kinase. Science 276:418–420, 1997
Frech M, John J, Pizon V, Chardin P, Tavitian A, Clark R, McCormick F, Wittinghofer A: Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product. Science 249:169–171, 1990
Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ: Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157, 1993
Sharfe N, Dadi HK, Shahar M, Roifman CM: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 94:3168–3171, 1997
Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA: Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7:679–689, 1997
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gesbert, F., Delespine-Carmagnat, M. & Bertoglio, J. Recent Advances in the Understanding of Interleukin-2 Signal Transduction. J Clin Immunol 18, 307–320 (1998). https://doi.org/10.1023/A:1023223614407
Issue Date:
DOI: https://doi.org/10.1023/A:1023223614407