Key Molecules Involved in Receptor‐Mediated Lymphocyte Activation

John J. O'Shea1, James A. Johnston2, John Kehrl3, Gary Koretzky4, Lawrence E. Samelson5

1 National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, 2 DNAX, Palo Alto, California, 3 National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, 4 University of Iowa College of Medicine, Iowa City, Iowa, 5 National Institute of Child Health and Human Development, Bethesda, Maryland
Publication Name:  Current Protocols in Immunology
Unit Number:  Unit 11.9A
DOI:  10.1002/0471142735.im1109as44
Online Posting Date:  November, 2001
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

This unit, along with Unit 11.9B, provides a summary of our current knowledge about various signaling pathways critical to the function of immune cells. Here, our understanding of T cell receptor (TCR)‐ and B cell receptor (BCR)‐mediated signaling is summarized. A schematic representation of immunologically relevant cytokine receptors and the Janus Family Kinases (JAKs) that is activated through these receptors is provided, along with details about molecules involved in interleukin 2 mediated signal transduction.

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Signaling Molecules
  • T Cell Receptor (TCR) Signal Transduction
  • B Cell Receptor (BCR) Signal Transduction
  • Signaling Via the Interleukin 2 Receptor (IL‐2R) and Related Receptors
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Adachi, M., Fischer, E.H., Ihle, J., Imai, K., Jirik, F., Neel, B., Pawson, T., Shen, S., Thomas, M., Ullrich, A., and Zhao, Z. 1996. Mammalian SH2‐containing protein tyrosine phosphatases. Cell 85:15.
   Appleby, M.W., Gross, J.A., Cooke, M.P., Levin, S.D., Qian, X., and Perlmutter, R.M. 1992. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell 70:751‐763.
   Arpaia, E., Shahar, M., Dadi, H., Cohen, A., and Roifman, C.M. 1994. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap‐70 kinase. Cell 76:947‐958.
   Bazan, J.F. 1990. Haemopoietic receptors and helical cytokines. Immunol. Today 11:350‐354.
   Boulton, T.G., Nye, S.H., Robbins, D.J., Ip, N.Y., Radziejewska, E., Morgenbesser, S.D., DePinho, R.A., Panayotatos, N., Cobb, M.H., and Yancopoulos, G.D. 1991. ERKs: A family of protein‐serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65:663‐675.
   Burgering, B.M. and Coffer, P.J. 1995. Protein kinase B (c‐Akt) in phosphatidylinositol‐3‐OH kinase signal transduction. Nature 376:599‐602.
   Chan, A.C., Iwashima, M., Turck, C.W., and Weiss, A. 1992. A 70 kD protein tyrosine kinase that associates with the TCR ζ chain. Cell 71:649‐662.
   Chan, A.C., Kadlecek, T.A., Elder, M.E., Filipovich, A.H., Kuo, W.L., Iwashima, M., Parslow, T.G., and Weiss, A. 1994. ZAP‐70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264:1599‐1601.
   Chardin, P., Camonis, J.H., Gale, N.W., van Aelst, L., Schlessinger, J., Wigler, M.H., and Bar‐Sagi, D. 1993. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260:1338‐1343.
   Cheng, A.M., Rowley, B., Pao, W., Hayday, A., Bolen, J.B., and Pawson, T. 1995. Syk tyrosine kinase required for mouse viability and B‐cell development. Nature 378:303‐306.
   Cosman, D. 1993. The hematopoietin receptor superfamily. Cytokine 5:95‐106.
   Crabtree, G.R. and Clipstone, N.A. 1994. Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu. Rev. Biochem. 63:1045‐1083.
   Cyster, J.G., Healy, J.I., Kishihara, K., Mak, T.W., Thomas, M.L., and Goodnow, C.C. 1996. Regulation of B‐lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381:325‐328.
   D'Ambrosio, D., Hippen, K.L., Minskoff, S.A., and Mellman, I. 1995. Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by FcλRIIB1. Science 268:293‐297.
   DeFranco, A.F. 1995. Transmembrane signaling by antigen receptors of B and T lymphocytes. Curr. Opin. Cell Biol. 7:163‐175.
   Donovan, J.A., Wange, R.L., Langdon, W.Y., and Samelson, L.E. 1994. The protein product of the c‐cbl protooncogene is the 120‐kDa tyrosine phosphorylated protein in Jurkat cells activated via the T cell antigen receptor. J. Biol. Chem. 269:22921‐22924.
   Doody, G.M., Justement, L.B., Delibrias, C.C., Matthews, R.J., Lin, J., Thomas, M.L., and Fearon, D.T. 1995. A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science 269:242‐244.
   Downward, J. 1996. Control of ras activation. Cancer Surv. 27:87‐100.
   Durbin, J.E., Hackenmiller, R., Simon, M.C., and Levy, D.E. 1996. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84:443‐450.
   Dymecki, S.M., Niederhuber, J.E., and Desiderio, S.V. 1990. Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. Science 247:332‐336.
   Elder, M.E., Lin, D., Clever, J., Chan, A.C., Hope, T.J., Weiss, A., Parslow, T.G. 1994. Human severe combined immunodeficiency due to a defect in ZAP‐70, a T cell tyrosine kinase. Science 264:1596‐1599.
   Fischer, K.D., Zmuldzinas, A., Gardner, S., Barbacid, M., Bernstein, A., Guidos, C. 1995. Defective T‐cell receptor signalling and positive selection of Vav‐deficient CD4+ CD8+ thymocytes. Nature 374:474‐477.
   Gong, S. and Nussenzweig, M.C. 1996. Regulation of an early developmental checkpoint in the B cell pathway by Igβ. Science 272:411‐414.
   Gross, J.A., Appleby, M.W., Chien, S., Nada, S., Bartelmez, S.H., Okada, M., Aizawa, S., and Perlmutter, R.M. 1995. Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase. J. Exp. Med. 181:463‐473.
   Hatakeyama, M., Kono, T., Kobayashi, N., Kawahara, A., Levin, S.D., Perlmutter, R.M., and Taniguchi, T. 1991. Interaction of the IL‐2 receptor with the Src‐family kinase p56lck: Identification of novel intermolecular association. Science 252:1523‐1528.
   Hibbs, M.L., Tarlinton, D.M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S.A., and Dunn, A.R. 1995. Multiple defects in the immune system of Lyn‐deficient mice, culminating in autoimmune disease. Cell 83:301‐311.
   Hou, J., Schindler, U., Henzel, W.J., Wong, S.C., and McKnight, S.L. 1995. Identification and purification of human Stat proteins activated in response to interleukin‐2. Immunity 2:321‐329.
   Ihle, J.N. 1995. Cytokine receptor signalling. Nature 377:591‐594.
   Ihle, J.N. 1996. Janus kinases in cytokine signalling. Phil. Trans. R. Soc. Lond. B Biol. Sci. 351:159‐166.
   Jackman, J.K., Motto, D.G., Sun, Q., Tanemoto, M., Turck, C.W., Peltz, G.A., Koretzky, G.A., and Findell, P.R. 1995. Molecular cloning of SLP‐76, a 76‐kDa tyrosine phosphoprotein associated with Grb2 in T cells. J. Biol. Chem. 270:7029‐7032.
   Jain, J., McCaffrey, P.G., Miner, Z., Kerppola, T.K., Lambert, J.N., Verdine, G.L., Curran, T., and Rao, A. 1993. The T‐cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 365:352‐355.
   Johnston, J.A., Kawamura, M., Kirken, R.A., Chen, Y.Q., Blake, T.B., Shibuya, K., Ortaldo, J.R., McVicar, D.W., and O'Shea, J.J. 1994. Phosphorylation and activation of the Jak‐3 Janus kinase in response to interleukin‐2. Nature 370:151‐153.
   Johnston, J.A., Bacon, C.M., Finbloom, D.S., Rees, R.C., Kaplan, D., Shibuya, K., Ortaldo, J.R., Gupta, S., Chen, Y.Q., Giri, J.D., and O'Shea, J.J. 1995a. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc. Natl. Acad. Sci. U.S.A. 92:8705‐8709.
   Johnston, J.A., Wang, L.M., Hanson, E.P., Sun, X.J., White, M.F., Oakes, S.A., Pierce, J.H., and O'Shea, J.J. 1995b. Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. J. Biol. Chem. 270:28527‐28530.
   Johnston, J.A., Bacon, C.M., Riedy, M.C., and O'Shea, J.J. 1996. Signaling by IL‐2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency. J. Leuk. Biol. 60:441‐452.
   Kaplan, M.H., Schindler, U., Smiley, S.T., and Grusby, M.J. 1996a. Stat6 is required for mediating responses to IL‐4 and for development of Th2 cells. Immunity. 4:313‐319.
   Kaplan, M.H., Sun, Y.L., Hoey, T., and Grusby, M.J. 1996b. Impaired IL‐12 responses and enhanced development of Th2 cells in Stat4‐deficient mice. Nature 382:174‐177.
   Kawamura, M., McVicar, D.W., Johnston, J.A., Blake, T.B., Chen, Y.Q., Lal, B.K., Lloyd, A.R., Kelvin, D.J., Staples, J.E., Ortaldo, J.R., et al. 1994. Molecular cloning of L‐JAK, a Janus family protein‐tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc. Natl. Acad. Sci. U.S.A. 91:6374‐6378.
   Lin, J.X., Migone, T.S., Tsang, M., Friedmann, M., Weatherbee, J.A., Zhou, L., Yamauchi, A., Bloom, E.T., Mietz, J., John, S., et al. 1995. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL‐2, IL‐4, IL‐7, IL‐13, and IL‐15. Immunity. 2:331‐339.
   Liu, X., Robinson, G.W., Gouilleux, F., Groner, B., and Hennighausen, L. 1995. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc. Natl. Acad. Sci. U.S.A. 92:8831‐8835.
   Macchi, P., Villa, A., Gillani, S., Sacco, MG., Frattini, A., Porta, F., Ugazio, A.G., Johnston, J.A., Candotti, F., O'Shea, J.J., Vezzani, P., and Notarangelo, L.D. 1995. Mutations of Jak‐3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:65‐68.
   Marth, J.D., Peet, R., Krebs, E.G., and Perlmutter, R.M. 1985. A lymphocyte‐specific protein‐tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell 43:393‐404.
   Meraz, M.A., White, J.M., Sheehan, K.C., Bach, E.A., Rodig, S.J., Dighe, A.S., Kaplan, D.H., Riley, J.K., Greenlund, A.C., Campbell, D., Carver‐Moore, K., DuBois, R.N., Clark, R., Aguet, M., and Schreiber. R.D. 1996. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK‐STAT signaling pathway. Cell 84:431‐442.
   Minami, Y., Nakagawa, Y., Kawahara, A., Miyazaki, T., Sada, K., Yamamura, H., and Taniguchi, T. 1995. 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.
   Motto, D.G., Musci, M.A., Ross, S.E., and Koretzky, G.A. 1996a. Tyrosine phosphorylation of pp36 is required for coupling the T cell antigen receptor with PLCγ1. Mol. Cell. Biol. 16:2823‐2828.
   Motto, D.G., Ross, S.E., Hendricks‐Taylor, L.R., Wu, J., and Koretzky, G.A. 1996b. Implication of the Grb2‐associated phosphoprotein SLP‐76 in TCR‐mediated IL‐2 production. J. Exp. Med. 183:1937‐1943.
   Nagai, K., Takata, M., Yamamura, H., and Kurosaki, T. 1995. Tyrosine phosphorylation of Shc is mediated through Lyn and Syk in B cell receptor signaling. J. Biol. Chem. 270:6824‐6829.
   Negishi, I., Motoyama, N., Nakayama, K., Nakayama, K., Senju, S., Hatakeyama, S., Zhang, Q., Chan, A.C., and Loh, D.Y. 1995. Essential role for ZAP‐70 in both positive and negative selection of thymocytes. Nature 376:435‐438.
   Nosaka, T., van Deursen, J.M., Tripp, R.A., Thierfelder, W.E., Witthuhn, B.A., McMickle, A.P., Doherty, P.C., Grosveld, G.C., and Ihle, J.N. 1995. Defective lymphoid development in mice lacking Jak3. Science 270:800‐802.
   Ota, Y. and Samelson, L.E. 1997. The product of the proto‐oncogene c‐cbl: A negative regulator of the Syk tyrosine kinase. Science 276:418‐420.
   Parker, P.J. and Waterfield, M.D. 1992. Phosphatidylinositol 3‐kinase: A novel effector. Cell Growth Differ. 3:747‐752.
   Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T., and Pelicci, P.G. 1992. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70:93‐104.
   Pingel, J.T. and Thomas, M.L. 1989. Evidence that the leukocyte‐common antigen is required for antigen‐induced T lymphocyte proliferation. Cell 58:1055‐1065.
   Pleiman, C.M., D'Ambrosio, D., and Cambier, J.C. 1994. The B‐cell antigen receptor complex: Structure and signal transduction. Immunol. Today 15:393‐406.
   Rapp, U.R., Heidecker, G., Huleihel, M., Cleveland, J.L., Choi, W.C., Pawson, T., Ihle, J.N., and Anderson, W.B. 1988. Raf family serine/threonine protein kinases in mitogen signal transduction. Cold Spring Harbor Symp. Quant. Biol. 53:Pt.1:173‐184.
   Ravichandran, K.S., Lee, K.K., Songyang, Z., Cantley, L.C., Burn, P., and Burakoff, S.J. 1993. Interaction of Shc with the ζ chain of the T cell receptor upon T cell activation. Science 262:902‐905.
   Rawlings, D.J. and Witte, O.N. 1994. Bruton's tyrosine kinase is a key regulator in B‐cell development. Immunol. Rev. 138:105‐119.
   Reth, M. 1995. The B‐cell antigen receptor complex and co‐receptors. Immunol. Today. 16:310‐313.
   Richards, J.D., Golds, M.R., Hourihane, S.L., DeFranco, A.L., and Matsuuchi, L. 1996. Reconstitution of B cell antigen receptor‐induced signaling events in a nonlymphoid cell line by expressing the Syk protein‐tyrosine kinase. J. Biol. Chem. 271:6458‐6466.
   Rudd, C.E. 1996. Upstream‐downstream: CD28 cosignaling pathways and T cell function. Immunity 4:527‐534.
   Russell, S.M., Johnston, J.A., Noguchi, M., Kawamura, M., Bacon, C.M., Friedmann, M., Berg, M., McVicar, D.W., Witthuhn, B.A., Silvennoinen, O., et al. 1994. Interaction of IL‐2R beta and gamma c chains with Jak1 and Jak3: Implications for XSCID and XCID. Science 266:1042‐1045.
   Russell, S.M., Tayebi, N., Nakajima, H., Riedy, M.C., Roberts, J.L., Aman, M.J., Migone, T.S., Noguchi, M., Markert, M.L., and Buckley, R.H. 1995. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development. Science 270:797‐800.
   Schindler, C. and Darnell, J.E. 1995. Transcriptional responses to polypeptide ligands: The JAK‐STAT pathway. Annu. Rev. Biochem. 64:621‐651.
   Shaw, A.S., Amrein, K.E., Hammond, C., Stern, D.F., Sefton, B.M., and Rose, J.K. 1989. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino‐terminal domain. Cell 59:627‐636.
   Shimoda, K., van Deursen, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp, R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A., Doherty, P.C., Grosveld, G., Paul, W.E., and Ihle, J.N. 1996. Lack of IL‐4‐induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630‐633.
   Skolnik, E.Y., Batzer, A., Li, N., Lee, C.H., Lowenstein, E., Mohammadi, M., Margolis, B., and Schlessinger, J. 1993. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 260:1953‐1955.
   Suh, P.G., Ryu, S.H., Moon, K.H., Suh, H.W., and Rhee, S.G. 1988. Cloning and sequence of multiple forms of phospholipase C. Cell 54:161‐169.
   Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., and Akira, S. 1996. Essential role of Stat6 in IL‐4 signalling. Nature 380:627‐630.
   Taniguchi, T. 1995. Cytokine signaling through nonreceptor protein tyrosine kinases. Science 268:251‐255.
   Taniuchi, I., Kitamura, D., Maekawa, Y., Fukuda, T., Kishi, H., and Watanabe, T. 1995. Antigen‐receptor induced clonal expansion and deletion of lymphocytes are impaired in mice lacking HS1 protein, a substrate of the antigen‐receptor‐coupled tyrosine kinases. EMBO J. 14:3664‐3678.
   Tedder, T.F., Zhou, L.J., and Engel, P. 1994. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol. Today 14:437‐442.
   Thierfelder, W.E., van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Sangster, M.Y., Vignali, D.A., Doherty, P.C., Grosveld, G.C., and Ihle, J.N. 1996. Requirement for Stat4 in interleukin‐12‐mediated responses of natural killer and T cells. Nature 382:171‐174.
   Thomis, D.C., Gurniak, C.B., Tivol, E., Sharpe, A.H., and Berg, L.J. 1995. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270:794‐797.
   Turner, M., Mee, P.J., Costello, P.S., Williams, O., Price, A.A., Duddy, L.P., Furlong, M.T., Geahlen, R.L., and Tybulewicz, V.L. 1995. Perinatal lethality and blocked B‐cell development in mice lacking the tyrosine kinase Syk. Nature 378:298‐302.
   Veillette, A., Bookman, M.A., Horak, E.M., and Bolen, J.B. 1988. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine‐protein kinase p56lck. Cell 55:301‐308.
   Voronova, A.F. and Sefton, B.M. 1986. Expression of a new tyrosine protein kinase is stimulated by retrovirus promoter insertion. Nature 319:682‐685.
   Wang, L.M., Keegan, A., Frankel, M., Paul, W.E., and Pierce, J.H. 1995. Signal transduction through the IL‐4 and insulin receptor families. Stem Cells (Dayt). 13:360‐368.
   Wange, R.L. and Samelson, L.E. 1996. Complex complexes: Signaling at the TCR. Immunity. 5:197‐205.
   Weiss, A., Koretzky, G., and Schatzman, R. 1991. Functional activation of the T cell antigen receptor induces tyrosine phosphorylation of phospholipase Cg1. Proc. Natl. Acad. Sci. U.S.A. 88:5484‐5488.
   White, M.F. 1996. The IRS‐signalling system in insulin and cytokine action. Phil. Trans. R. Soc. Lond. B Biol. Sci. 351:181‐189.
   Wilks, A.F., Harpur, A.G., Kurban, R.R., Ralph, S.J., Zurcher, G., and Ziemiecki, A.. 1991. Two novel protein‐tyrosine kinases, each with a second phosphotransferase‐related catalytic domain, define a new class of protein kinase. Mol. Cell Biol. 11:2057‐2065.
   Witthuhn, B.A., Silvennoinen, O., Miura, O., Lai, K.S., Cwik, C., Liu, E.T., and Ihle, J.N. 1994. Involvement of the Jak‐3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370:153‐157.
   Woodrow, M., Clipstone, N.A., and Cantrell, D. 1993. p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells. J. Exp. Med. 178:1517‐1522.
   Zhang, R., Alt, F.W., Davidson, L., Orkin, S.H., and Swat, W. 1995. Defective signalling through the T‐ and B‐cell antigen receptors in lymphoid cells lacking the vav proto‐oncogene. Nature 374:470‐473.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library