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EJB Reviews pp 27-41 | Cite as

T-cell antigen receptor-induced signal-transduction pathways Activation and function of protein kinases C in T lymphocytes

  • Marta Szamel
  • Klaus Resch
Part of the European Journal of Biochemistry book series (EJB REVIEWS, volume 1995)

Abstract

The specificity of the immune response is determined by the interaction between T-cell antigen receptor and its cognate antigen. The T-cell antigen receptor and several coreceptors initiate parallel and interdependent signal transduction pathways. Protein-tyrosine phosphorylation is important in the initiation of cellular responses by the T-cell antigen receptor. As the T-cell receptor has no intrinsic protein-tyrosine kinase activity, activation of cytoplasmic non-receptor tyrosine-protein kinases is critical to the activation of lymphocytes. Both the src family of tyrosine kinases and the sck family of tyrosine-protein kinases play a role in T lymphocyte activation. The T-cell antigen receptor is coupled to this cluster of kinases by the cytoplasmic tails of the CD3 subunits. The distinct protein-tyrosine kinases interact with the T-cell receptor as well as with each other. At least one phosphoprotein phosphatase, CD45, can positively or negatively influence the T-cell receptor-induced signaling by dephosphorylating either src-related protein kinases or the receptor components.

Keywords

T-lymphocyte T-cell activation signal transduction protein kinase C 

Abbreviations

IL-2

interleukin-2

MAP

mitogen-activated protein

MHC

major histocompatibility complex

EGF

epidermal growth factor

PDGF

platelet-derived growth factor

SH

src homology

PtdIns

phosphatidylinositol

GAP

GTPaseactivating protein

PtdIns(4,5)P2

phosphatidylinositol 4,5-bisphosphate

InsP3

inositol 1,4,5-trisphosphate

PtdIns(3,4)P2

phosphatidylinositol 3,4-bisphosphate

Ins(3,4,5)P3

inositol 3,4,5-trisphosphate

NF-AT

nuclear factor of activated T-cells

PKC

protein kinase C

PLA2

phospholipase A2

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References

  1. Abraham, N., Miceli, M. C., Parnes, J. R. and Veillette, A. (1991) Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56, Nature 350, 62–66.PubMedGoogle Scholar
  2. Amrein, K. E., Panholzer, B., Flint, N. A., Bannwarth, W. and Burn, R (1993) The Src homology 2 domain of the protein-tyrosine kinase p56 mediates both intermolecular and intramolecular interactions, Proc. Natl Acad. Sci. USA 90,10285–10289.PubMedGoogle Scholar
  3. Appleby, M. W., Gross, J. A., Cooke, M. R, Levin, S. D., Qian, X. and Perlmutter, R. M. (1992) Defective T cell receptor signaling in mice lacking the thymic isoform of p59, Cell 70, 751–763.PubMedGoogle Scholar
  4. Asaoka, Y., Oka, M., Yoshida, K. and Nishizuka, Y. (1991) Metabolic rate of membrane-permeant diacylglycerol and its relation to human resting T-lymphocyte activation, Proc. Natl Acad. Sci. USA 88, 8681– 8685.PubMedGoogle Scholar
  5. Asaoka, Y, Nakamura, S., Yoshida, K. and Nishizuka, Y. (1992) Protein kinase C, calcium and phospholipid degradation, Trends Biochem. Sci 17, 414–417.PubMedGoogle Scholar
  6. Asaoka, Y., Oka, M., Yoshida, K., Sasaki, Y. and Nishizuka, Y. (1992a) Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C, Proc. Natl Acad. Sci. USA 89, 6447–6451.PubMedGoogle Scholar
  7. Asaoka, Y.. Yoshida, K., Sasaki, Y., Nishizuka, Y., Murakami, M., Kudo, I. and Inoue, K. (1993) Possible role of mammalian secretory group II phospholipase A2 in T-lymphocyte activation: implication in propagation of inflammatory reaction, Proc. Natl Acad. Sci. USA 90, 716–719.PubMedGoogle Scholar
  8. Autero, M., Saharinen, J., Pessa-Morikawa, T., Soula-Rothhut, M., Oetken, C., Gassmann, M., Bergman, M., Alitalo, K., Bum, R, Gahmberg, C. G. (1994) Tyrosine phosphorylation of CD45 phosphotyrosine phosphatase by p50`sk kinase creates a binding site for p56 tyrosine kinase and activates the phosphatase, Mol. Cell. Biol. 14, 13008–13021.Google Scholar
  9. Baldari, C. T., Macchia, G. and Telford, J. L. (1992) Interleukin-2 promoter activation in T cells expressing activated Ha-ras, J. Biol. Chem 267, 4289–4291.PubMedGoogle Scholar
  10. Baldari, C. T., Heguy, A. and Telford. J. L. (1993) Calcium dependent activation of the NF-AT transcription factor by p59`“, FEBS Lett. 323, 233–235.PubMedGoogle Scholar
  11. Baldari, C. T., Heguy, A. and Telford, J. L. (1993) Aras protein activity is essential for T-cell antigen receptor signal transduction, J. Biol. Chem 268, 2693–2698.PubMedGoogle Scholar
  12. Berra, E., Diaz-Meco, M. T., Dominguez, I., Municio, M. M., Sanz, L., Lozano, J., Chapkin, R. S. and Moscat, J. (1993) Protein kinase C isoform is critical for mitogenic signal transduction, Cell 74, 555–563.PubMedGoogle Scholar
  13. Berridge, M. J. (1993) Inositol trisphosphate and calcium signalling, Nature 361, 315–325.PubMedGoogle Scholar
  14. Berry, N., Ase, K., Kikkawa, U., Kishimoto, A. and Nishizuka, Y. (1989) Human T cell activation by phorbol esters and diacylglycerol analogues, J. Immunol. 143, 1407 —1413.PubMedGoogle Scholar
  15. Berry, N. and Nishizuka, Y. (1990) Protein kinase C and T cell activation, Eur. J. Biochem 189, 205–214.PubMedGoogle Scholar
  16. Berry, N., Ase, K., Kishimoto, A. and Nishizuka, Y. (1990) Activation of resting human T cells requires prolonged stimulation of protein kinase C, Proc. Natl Acad. Sci. USA 87, 2294–2298.PubMedGoogle Scholar
  17. Biffen, M., Shiroo, M. and Alexander, D. R. (1993) Selective coupling of the T cell antigen receptor to phosphoinositol-derived diacylglycerol production in HPB-ALL T cells correlates with CD45-regulated p591“ activity, Eur. J. Immunol 23, 2980–2987.PubMedGoogle Scholar
  18. Billah, M. M. (1993) Phospholipase D and cell signaling, CWT. Opin. Immunol 5, 114–123.Google Scholar
  19. Birchall, A. M., Bishop, J., Bradshaw, D., Cline, A., Coffey, J., Elliott, L. H. (1994) Ro32–0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation, J. Pharmacol. Exp. Ther 268, 922–929.PubMedGoogle Scholar
  20. van Blitterswijk, W. J., Hilkmann, H., de Widt, J. and van der Bend, R. L. (1991) Phospholipd metabolism in bradykinin-stimulated human fibroblasts. I. Biphasic formation of diacylglycerol from phosphatidylinositol and phosphatidylcholine, controlled by protein kinase C, J. Biol. Chem 266, 10337–10343.PubMedGoogle Scholar
  21. van Blitterswijk, W. J., Hilkmann, H., de Widt, J. and van der Bend, R. L. (1991) Phospholipid metabolism in bradykinin-stimulated human fibroblasts. H. Phosphatidylcholine breakdown by phospholipases C and D; involvement of protein kinase C, J. Biol. Chem 266, 10344–10350.Google Scholar
  22. Boarder, M. R. (1994) A role of phospholipase D in control of mitogenesis, Trends Pharmacol. Sci 15, 57–62.PubMedGoogle Scholar
  23. Böl, G. F., Haack, B. M. and Resch, K. (1993) CD2 dependence of the chain in T cell signalling — shown by inhibitory and modifying effects of cholera toxin, NATO ASI See. H76, 343.Google Scholar
  24. Buday, L. and Downward, J. (1993) Epidermal growth factor regulates p21`’s through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor, Cell 73, 611–620.PubMedGoogle Scholar
  25. Buday, L., Egan, S. E., Rodriguez-Vicina, E, Cantrell, D. A. and Downward, J. (1994) A complex of Grb2 adaptor protein. Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells, J. Biol. Chem 269, 9019–9023.PubMedGoogle Scholar
  26. Burgess, K. E., Odysseos, A. D., Zalvan, C., Druker, B. J., Anderson, P., Schlossman, S. F. and Rudd, C. E. (1991) Biochemical identification of a direct physical interaction between the CD4:p56’`k and Ti(TcR)CD3 complexes, Eur. J. Immunol 21, 1663–1668.PubMedGoogle Scholar
  27. Cai, H., Erhardt, R, Troppmair, J., Diaz-Meco, M. T., Sithanandam, G., Rapp, U. R.. Moscat, J. and Cooper, G. M. (1993) Hydrolysis of phosphatidylcholine couples ras to activation of Raf protein kinase during mitogenic signal tranduction, Mol. Cell. Biol I3, 7645–7651.Google Scholar
  28. Cantley, L. C., Auger, K. R., Carpenter, C., Duckworth, B., Graziani, A., Kapeller, R. and Soltoff, S. (1991) Oncogens and signal transduction, Cell 64, 281–302.PubMedGoogle Scholar
  29. Cantrell, D. A. (1994) G proteins in lymphocyte signaling, Curr. Opin. Immunol 6, 380–384.PubMedGoogle Scholar
  30. Cazaubon, S. M. and Parker, R J. (1993) Identification of the phosphorylated region responsible for the permissive activation of protein kinase C, J. Biol. Chem. 268, 17559–17563.PubMedGoogle Scholar
  31. Chan, A. C., Irving. B. A., Fraser, J. D. and Weiss, A. (1991) The chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein, Proc. Natl Acad. Sci. USA 88, 9166–9170.Google Scholar
  32. Chan, A. C., Iwashima, M., Turck, C. W. and Weiss, A. (1992) ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR chain, Cell 71, 649–662.PubMedGoogle Scholar
  33. Chow, L. M., Fournel, M., Davidson, D. and Veillette, A. (1993) Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50`sk Nature 365, 156–160.PubMedGoogle Scholar
  34. Clipstone, N. A. and Crabtree, G. R. (1993) Calcineurin is a key signaling enzyme in T lymphocyte activation and the target of the immunosuppressive drugs cyclosporin A and FK506, Ann. NY Acad. Sci 696, 20–30.PubMedGoogle Scholar
  35. Collins, T. L., Kassner, R. D., Bierer, B. E. and Burakoff, S. J. (1994) Adhesion receptors in lymphocyte activation, Cure Opin. Immunol 6, 385–393.Google Scholar
  36. Cooke, M. P., Abraham, K. M., Forbush, K. A. and Perlmutter, R. M. (1991) Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59`Y“), Cell 65, 281–291.PubMedGoogle Scholar
  37. Szamel and Resch (Eur. J. Biochem. 228) Google Scholar
  38. Cooper, J. A., Gould, K. A., Cartwright, C. A. and Hunter, T. (1986) Tyr527 is phosphorylated in pp60c-src: implication for regulation, Science 231, 1431–1434.PubMedGoogle Scholar
  39. Comicode, K. M., Smith, J. H., Bums, D. L. and Exton, J. H. (1994) Phospholipase D activation in fibroblast membranes by the a and /3 isoforms of protein kinase C, FEBS Lett. 342, 76–80.Google Scholar
  40. Danielian, S., Alcover, A., Polissard, L., Stefanescu, M., Acuto, O., Fischer, S. and Fagard, R. (1992) Both T cell receptor (TcR)-CD3 complex and CD2 increase the tyrosine kinase activity of p56’`k. CD2 can mediate TcR-CD3-independent and CD45-dependent activation of p56’`’`, Eur. J. Immunol 22, 2915–2921.PubMedGoogle Scholar
  41. Dasgupta, J. D., Granja, C., Druker, B., Lin, L. L., Yunis, E. J. and Relias, V. (1992) Phospholipase C-y-1 association with CD3 structure in T cells, J. Exp. Med 175, 285–288.PubMedGoogle Scholar
  42. Davidson, D., Chow, L. M., Foumel, M. and Veillette, A. (1992) Differential regulation of T cell antigen responsiveness by isoforms of the src-related tyrosine protein kinase p59, J. Exp. Med. 175, 1483 —1492.PubMedGoogle Scholar
  43. Davies, A. A., Ley, S. C. and Crumpton, M. J. (1992) CD5 is phosphorylated on tyrosine after stimulation of the T-cell antigen receptor complex, Proc. Natl Acad. Sci. USA 89, 6368–6372.PubMedGoogle Scholar
  44. Dekker, L. V. and Parker, P. J. (1994) Protein kinase C — a question of specificity, Trends Biochem. Sci 19, 73–77.PubMedGoogle Scholar
  45. Diaz-Meco, M. T., Berra, E., Municio, M. M., Sanz, L., Lozano, J., Dominguez, I., Diaz-Golpe, V., Lain de Lera, M. T., Alcami, J., Paya, C. V., Arenzana, S. E, Virelizier, J. L. and Moscat, J. (1993) A dominant negative protein kinase C ç subspecies blocks NF-KB activation, Mol. Cell. Biol 13, 4770–4775.PubMedGoogle Scholar
  46. Dominguez, I., Sanz, L., Arenzana,-Seisdedos, F., Diaz-Meco, M. T., Virelizier, J. L. and Moscat, J. (1993) Inhibition of protein kinase C subspecies blocks the activation of an NF-x B-like activity in Xeno-pus laevis oocytes, Mol. Cell. Biol 13, 1290–1295.Google Scholar
  47. Downward, J., Graves, J. D., Warne, P. H., Rayter, S. and Cantrell, D. A. (1990) Stimulation of p21`as upon T-cell activation, Nature 346, 719–723.PubMedGoogle Scholar
  48. Downward, J., Graves, J. and Cantrell, D. (1992) The regulation and function of p21 ras in T cells, Immunol. Today 13, 89–92.PubMedGoogle Scholar
  49. Egan, S. E., Giddings, B. W., Brooks, M. W., Buday, L., Sizeland, A. M. and Weinberg, R. A. (1993) Association of SosRas exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation, Nature 363, 45–51.PubMedGoogle Scholar
  50. Eldar, H., Ben-Av, P., Schmidt, U. S., Livneh, E. and Liscovitch, M. (1993) Up-regulation of phospholipase D activity induced by overexpression of protein kinase C-a. Studies in intact Swiss/3T3 cells and in detergent-solubilized membranes in vitro, J. Biol. Chem 268, 12560–12564.PubMedGoogle Scholar
  51. Egerton, M., Ashe, O. R., Chen, D., Druker, B. J., Burgess, W. H. and Samelson, L. E. (1992) VCP, the mammalian homolog of cdc48 is tyrosine phosphorylated in response to T cell antigen receptor activation, EMBO J. 11, 3533–3540.PubMedGoogle Scholar
  52. Exton, J. H. (1990) Signaling through phosphatidylcholine breakdown, J. Biol. Chem 265, 1–4.PubMedGoogle Scholar
  53. Fraser, J. D., Straus, D. and Weiss, A. (1993) Signal transduction events leading to T-cell lymphokine gene expression, Immunol. Today 14, 357–362.PubMedGoogle Scholar
  54. Gilliland, L. K., Schieven, G. L., Norris, N. A., Kanner, S. B., Aruffo, A. and Ledbetter, J. A. (1992) Lymphocyte lineage-restricted-tyrosinephosphorylated proteins that bind PLC-y-1 SH2 domains, J. Biol. Chem. 267, 13610–13616.PubMedGoogle Scholar
  55. Gold, M. R. and Aebersold, R. (1994) Both phosphatidylinositol 3-kinase and phosphatidylinositol 4-kinase products are increased by antigen receptor signaling in B cells, J. Immunol 152, 42–50.PubMedGoogle Scholar
  56. Gulbins, E., Coggeshall, K. M., Baier, G., Katzav, S., Burn, P. and Altman, A. (1993) Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation, Science 260, 822–825.PubMedGoogle Scholar
  57. Ha, K. S. and Exton, J. H. (1993) Differential translocation of protein kinase C isozymes by thrombin and platelet-derived growth factor. A possible function for phosphatidylcholine-derived diacylglycerol, J. Biol. Chem 268, 10534–10539.PubMedGoogle Scholar
  58. Haack, B. M., Emmrich, E. and Resch, K. (1993) Cholera toxin inhibits T cell receptor signaling by covalent modification of the CD3- subunit, J. Immunol. 150, 2599–2606.PubMedGoogle Scholar
  59. Hallberg, B., Rayter, S. I. and Downward, J. (1994) Interaction ofRas and Raf in intact mammalian cells upon extracellular stimulation, J. Biol. Chem 269, 3913–3916.PubMedGoogle Scholar
  60. Harwood, A. E. and Cambier, J. C. (1993) B cell antigen receptor cross-linking triggers rapid protein kinase C independent activation of p21`a51, J. Immunol. 151, 4513–4522.PubMedGoogle Scholar
  61. Hermans, M. H. and Malissen, B. (1993) The cytoplasmic tail of the T cell receptor chain is dispensable for antigen-mediated T cell activation, Eur. J. Immunol 23, 2257–2262.PubMedGoogle Scholar
  62. Howe, L. R. and Marshall, C. J. (1993) Lysophosphatidic acid stimulates mitogen-activated protein kinase activation via a G-protein-coupled pathway requiring p21’“ and p74raf-1, J. Biol. Chem 268, 20717–20720.PubMedGoogle Scholar
  63. Hug, H. and Sarre, T. E. (1993) Protein kinase C isoenzymes, divergence in signal transduction? Biochem. J 291, 329–343.PubMedGoogle Scholar
  64. Hurley, T. R., Hyman, R. and Sefton, B. M. (1993) Differential effects of expression of the CD45 tyrosine protein phosphatase on the tyrosine phosphorylation of the lck, fyn, and c-src tyrosine protein kinases, Mol. Cell. Biol 13, 1651–1656.PubMedGoogle Scholar
  65. Imboden, J. B. and Stobo, J. D. (1985) Transmembrane signaling by the T cell antigen receptor: perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores, J. Exp. Med 161, 446–456.PubMedGoogle Scholar
  66. Irving, B. A. and Weiss, A. (1991) The cytoplasmic domain of the T cell receptor chain is sufficient to couple to receptor-associated signal transduction pathways, Cell 64, 891–901.PubMedGoogle Scholar
  67. Irving, B. A., Chan, A. C. and Weiss, A. (1993) Functional characterization of a signal transducing motif present in the T cell antigen receptor chain, J. Exp. Med 177, 1093–1103.PubMedGoogle Scholar
  68. Isakov, N. (1993) Activation of murine lymphocytes by exogenous phosphatidylethanolamine-and phosphatidylcholine-specific phospholipase C, Cell. Immunol 152, 72–81.PubMedGoogle Scholar
  69. Isakov, N., Wange. R. L. and Samelson, L. E. (1994) The role of tyrosine kinases and phosphotyrosine-containing recognition motifs in regulation of the T cell-antigen receptor-mediated signal transduction pathway, J. Leukoc. Biol 55, 265–271.Google Scholar
  70. Iwashima, M., Irving, B. A., van Oers, N. S., Chan, A. C. and Weiss, A. (1994) Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases, Science 263, 1136–1139.PubMedGoogle Scholar
  71. Izquierdo, M., Downward, J., Graves, J. D. and Cantrell, D. A. (1992) Role of protein kinase C in T-cell antigen receptor regulation of p21’as: evidence that two p2lras regulatory pathways coexist in T cells, Mol. Cell. Biol 12, 3305–3312.PubMedGoogle Scholar
  72. Izquierdo, M. and Cantrell, D. A. (1993) Protein-tyrosine kinases couple the interleukin-2 receptor to p21’as, Eur. J. Immunol 23, 131–135.PubMedGoogle Scholar
  73. Izquierdo, M., Leevers, S. J., Marshall, C. J. and Cantrell, D. (1993) p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes, J. Exp. Med 178, 1199–1208.Google Scholar
  74. Johannes, E J., Prestle, J., Eis, S., Oberhagemann, P. and Pfitzenmaier, K. (1994) PKCIs is a novel atypical member of the protein kinase C family, J. Biol. Chem 269, 6140–6148.PubMedGoogle Scholar
  75. June, C. H., Fletcher, M. C., Ledbetter, J. A., Schieven, G. L., Siegel, J. N., Phillips, A. F. and Samelson, L. E. (1990) Inhibition of tyrosine phosphorylation prevents T-cell receptor-mediated signal transduction, Proc. Natl Acad. Sci. USA 87, 7722–7726.PubMedGoogle Scholar
  76. June, C. H., Bluestone, J. A., Nadler, L. M. and Thompson, C. B. (1994) The B7 and CD28 receptor families, Immunol. Today 15, 321–331.PubMedGoogle Scholar
  77. Justement, L. B., Campbell, K. S., Chien, N. C. and Cambier, J. C. (1991) Regulation of B cell antigen receptor signal transduction and phosphorylation by CD45, Science 252, 1839–1842.PubMedGoogle Scholar
  78. Kazanietz, M. G., Areces, L. B., Bahador, A., Mischak, H., Goodnight, J., Mushinski, J. F. and Blumberg, P. M. (1993) Characterization of ligand and substrate specificity for the calcium-dependent and calcium-independent protein kinase C isoenzymes, Mol. Pharmacol 44, 298–307.PubMedGoogle Scholar
  79. Keegan, A. D. and Paul, W. E. (1992) Multichain immune recognition receptors: similarities in structure and signaling pathways, Immunol. Today 13, 63–68.PubMedGoogle Scholar
  80. Kochs, G., Hummel, R., Meyer, D., Hug, H., Marine, D. and Sarre, T. F. (1993) Activation and substrate specificity of the human protein kinase C a and isoenzymes, Eur. J. Biochem 216, 597–606.PubMedGoogle Scholar
  81. Koide, H., Satoh, T., Nakafuku, M. and Kaziro, Y. (1993) GTP-dependent association of Raf-1 with Ha-Ras: identification of Raf as a target downstream ofRas in mammalian cells, Proc. Natl Acad. Sci. USA 90, 8683–8686.PubMedGoogle Scholar
  82. Kolanus, W., Romeo, C. and Seed, B. (1993) T cell activation by clustered tyrosine kinases, Cell 74, 171–183.PubMedGoogle Scholar
  83. Kolch, W., Heidecker, G., Kochs, G., Hummel, R., Vahidi, H., Mischak, H., Finkenzeller, G., Manne, D. and Rapp, U. R. (1993) Protein kinase C-a activates RAF-1 by direct phosphorylation, Nature 364, 249252.Google Scholar
  84. Koretzky, G. A., Picus, J., Schultz, T. and Weiss, A. (1990) Tyrosine phosphatase CD45 is required for T cell antigen receptor and CD2-mediated activation of a protein-tyrosine kinase and interleukin 2 production, Proc. Natl Acad. Sci. USA 88, 2037–2041.Google Scholar
  85. Kracht, M., Heiner, A., Resch, K. and Szamel, M. (1993) Interleukín-1induced signaling in T-cells. Evidence for the involvement of phosphatases PP1 and PP2A in regulating protein kinase C-mediated protein phosphorylation and interleukin-2 synthesis, J. Biol. Chem 268, 21066–21072.PubMedGoogle Scholar
  86. Krook, A., Rapoport, M. J., Anderson, S., Pross, H., Zhou, Y. C., Denhardt, D. T., Delovitch, T. L. and Haliotis, T. (1993) p21’ and protein kinase C function in distinct and interdependent signaling pathways in C3H 10T1/2 fibroblasts, Mol. Cell. Biol 13, 1471 1479.Google Scholar
  87. Leach, K. L., Ruff, V. A., Wright, T. M., Pessin, M. S. and Raben, D. M. (1991) Dissociation of protein kinase C activation and sn-1,2diacylglycerol formation. Comparison of phosphatidylinositol-and phosphatidylcholine-derived diacylglycerols in a-thrombin-stimulated fibroblasts, J. Biol. Chem 266, 3215–3221.PubMedGoogle Scholar
  88. Letourneur, F. and Klausner, R. D. (1992) Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3-e, Science 255, 79–82.PubMedGoogle Scholar
  89. Li, W., Mishak, H., Yu, J. C., Wang, L. M., Mushinski, J. F., Heidaran, M. A. and Pierce, J. H. (1994) Tyrosine phosphorylation of protein kinase C-b in response to its activation, J. Biol. Chem 269, 2349–2352.PubMedGoogle Scholar
  90. Liao, R, Shin, H. S. and Rhee, S. G. (1993) In vitro tyrosine phosphorylation of PLC-y-1 and PLC-y-2 by src-family protein-tyrosine kinases, Biochem. Biophys. Res. Commun 191, 1028–1033.Google Scholar
  91. Lin, P., Fung, W. J. and Gilfillan, A. M. (1992) Phosphatidylcholine-specific phospholipase D-derived 1,2-diacylglycerol does not initiate protein kinase C activation in the RBL 2H3 mast-cell line, Biochem. J 287, 325–331.PubMedGoogle Scholar
  92. Liscovitch, M., Ben-Av, P., Danin, M., Faiman, G, Eldar, H. and Livneh, E. (1993) Phospholipase D-mediated hydrolysis of phosphatidyl-choline, role in cell signalling, J. Lipid Mediat 8, 177–182.PubMedGoogle Scholar
  93. Malissen, B. and Schmitt-Verhulst, A. M. (1993) Transmembrane signalling through the T-cell-receptor-CD3 complex, Cure. Opin. Immunol 5, 324–333.Google Scholar
  94. Malissen, B., Wegener, A. M., Hoeveler, A. and Marguet, D. (1993) Molecular dissection of the T-cell receptor/CD3 complex, Immunol. Ser 59, 29–40.PubMedGoogle Scholar
  95. Manolios, N., Letourneur, F., Bonifacino, J. S. and Klausner, R. D. (1991) Pairwise, cooperative and inhibitory interactions describe the assembly and probable structure of the T-cell antigen receptor, EMBO J. 10, 1643 —1651.PubMedGoogle Scholar
  96. Marshall, M. S. (1993) The effector interactions of p2l, Trends Biochem. Sci 18, 250–254.PubMedGoogle Scholar
  97. McCormick, E (1993) Signal transduction. How receptors turn ras on, Nature 363, 15–16.PubMedGoogle Scholar
  98. McFarland, E. D., Hurley, T. R., Pingel, J. T., Sefton, B. M., Shaw, A. and Thomas, M. L. (1993) Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor, Proc. Natl Acad. Sci. USA 90, 1402–1406.Google Scholar
  99. Medema, R. H., de Vries Smits, A. M., van der Zon, G. C., Maassen, J. A. and Bos, J. L. (1993) ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides of p21T“s Mol. Cell. Biol 13, 155–162.Google Scholar
  100. Mishak, H., Goodnight, J., Henderson, D. W., Osada, S., Ohno, S. and Mushinski, J. F. (1993) Unique expression pattern of protein kinase C-9: high mRNA levels in normal mouse testes and in T-lymphocytic cells and neoplasmas, FEBS Lett. 326, 51–55.Google Scholar
  101. Mishak, H., Pierce, J. H., Goodnight, J., Kazanietz, M. G., Blumberg, P. M. and Mushinski, J. F. (1993a) Phorbol ester-induced myeloid differ-entiation is mediated by protein kinase C-a and -6 and not by protein kinase C-ß II, -e, -e’, and -rl, J. Biol. Chem 268, 20110–20115.Google Scholar
  102. Murray, N. R., Baumgardner, G. P., Burns, D. J. and Fields, A. P. (1993) Protein kinase C isotypes in human erythroleukemia (K562) cell proliferation and differentiation. Evidence that ß II protein kinase C is required for proliferation, J. Biol. Chem 268, 15847–15853.PubMedGoogle Scholar
  103. Mustelin, T., Coggeshall, K. M. and Altman, A. (1989) Rapid activation of the T-cell tyrosine protein kinase pp56’`k by the CD45 phosphotyrosine phosphatase, Proc. Natl Acad. Sci. USA 86, 6302–6306.PubMedGoogle Scholar
  104. Mustelin, T. and Bum, P. (1993) Regulation of src family tyrosine kinases in lymphocytes, Trends Biochem. Sci 18, 215–220.PubMedGoogle Scholar
  105. Nakamura, S., Asaoka, Y., Yoshida, K., Sasaki, Y. and Nishizuka, Y. (1993) Protein kinase C for cell signaling: a possible link between phospholipases, Adv. Sec. Messenger Phosphoprotein Res 28, 171–178.Google Scholar
  106. Nakanishi, H., Brewer, K. A. and Exton, J. H. (1993) Activation of the isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem, 268, 13–16.PubMedGoogle Scholar
  107. Nishizuka, Y. (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion, Nature 308, 693–697.PubMedGoogle Scholar
  108. Nishizuka, Y. (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C, Science 258, 607–614.PubMedGoogle Scholar
  109. Nishizuka, Y. (1992a) Membrane phospholipid degradation and protein kinase C for cell signalling, Neurosci. Res. NY 15, 3–5.Google Scholar
  110. Okada, M., Nada, S., Yamanashi, Y., Yamamoto, T. and Nakagawa, H. (1991) CSK: a protein-tyrosine kinase involved in regulation of src family kinases, J. Biol. Chem 266, 24249–24252.PubMedGoogle Scholar
  111. Pai, J. K., Pachter, J. A., Weinstein, I. B. and Bishop, W. R. (1991) Over-expression of protein kinase C-ß 1 enhances phospholipase D activity and diacylglycerol formation in phorbol-ester-stimulated rat fibroblasts, Proc. Natl Acad. Sci. USA 88, 598–602.PubMedGoogle Scholar
  112. Pears, C, Stabel, S, Cazaubon, S and Parker, PJ. (1992) Studies on the phosphorylation of protein kinase C-a, Biochem. J 283, 515–518.Google Scholar
  113. Penninger, J. M., Wallace, V. A., Kishihara, K. and Mak, T. W. (1993) The role of p56’`k and p59fY“ tyrosine kinases and CD45 protein tyrosine phosphatase in T-cell development and clonal selection, Immunol. Rev 135, 183–214.PubMedGoogle Scholar
  114. Peter, M. E., Hall, C., Ruhlmann, A., Sancho, J. and Terhorst, C. (1992) The T-cell receptor chain contains a GTP-GDP binding site, EMBO J. 11, 933–941.PubMedGoogle Scholar
  115. Pfeffer, L. M., Strulovici, B. and Saltiel, A. R. (1990) Interferon-alpha selectively activates the ß isoform of protein kinase C through phosphatidylcholine hydrolysis, Proc. Natl Acad. Sci. USA 87, 6537–6541.PubMedGoogle Scholar
  116. Pfeilschifter, J. and Huwiler, A. (1993) A role for protein kinase C-epsilon in angiotensin II stimulation of phospholipase D in rat renal mesangial cells, FEBS Lett. 331, 267–271.PubMedGoogle Scholar
  117. Pleiman, C. M, Clark, M. R., Gauen, L. K, Winitz, S., Coggeshall, K. M., Johnson, G. L., Shaw, A. S. and Cambier, J. C. (1993) Mapping of sites on the Src family protein-tyrosine kinases, and p56`Y“ which interact with the effector molecules phospholipase C-y 2, microtubule-associated protein kinase, GTPase activating protein, and phosphatidylinositol 3-kinase, Mol. Cell. Biol 13, 5877–5887.PubMedGoogle Scholar
  118. Polakis, P. and McCormick, F. (1993) Structural requirements for the interaction of p21`ß with GAP, exchange factors, and its biological effector target, J. Biol. Chem 268, 9157–9160.PubMedGoogle Scholar
  119. Prasad, K. V., Kapeller, R., Janssen, O., Repke, H., Duke-Cohan, J. S., Cantley, L. E. and Rudd, C. E. (1993) Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56’ complex: the p56 SH3 domain binds to PI 3-kinase but not PI 4-kinase, Mol. Cell. Biol 13, 7708–7717.PubMedGoogle Scholar
  120. Prasad, K. V., Janssen, O., Kapeller, R., Raab, M., Cantley, L. C. and Rudd, C. E. (1993a) Src-homology 3 domain of protein kinase p59ú“” mediates binding to phosphatidylinositol 3-kinase in T cells, Proc. Natl Acad. Sci. USA 90, 7366–7370.PubMedGoogle Scholar
  121. Rapp, U. R. (1991) Role of Raf-1 serine/threonine protein kinase in growth factor signal transduction, Oncogene 6, 495–500.PubMedGoogle Scholar
  122. Rao, A. (1994) NF-ATp, a transcription factor required for the coordinate induction of several cytokine genes, Immunol. Today 15, 274–281.PubMedGoogle Scholar
  123. Rayter, S. I., Woodrow, M., Lucas, S. C., Cantrell, D. A. and Downward, J. (1992) p21“s mediates control of IL-2 gene promoter function in T cell activation, EMBO J. 11, 4549–4556.Google Scholar
  124. Ravichandran, K. S., Lee, K. K., Songyang, Z., Cantley, L. C., Burn, P. and Burakoff, S. J. (1993) Interaction of Shc with the chain of the T cell receptor upon T cell activation, Science 262, 902–905.PubMedGoogle Scholar
  125. Romeo, C. and Seed, B. (1991) Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides, Cell 64, 1037–1046.PubMedGoogle Scholar
  126. Romeo, C., Amiot, M. and Seed, B. (1992) Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor -chain, Cell 68889–897Google Scholar
  127. Rudd, C. E., Janssen, O., Prasad, K. V., Raab, M., da Silva, A., Telfer,J. C. and Yamamoto, M. (1993) Src-related protein-tyrosine kinases and their surface receptors, Biochim. Biophys. Acta 1155, 239–266.PubMedGoogle Scholar
  128. Rudd, C. E., Janssen, O., Cai, Y. C., da Silva, A. J., Raab M. and Prasad K. V. S. (1994) Two step TCR-/CD3–CD4 and CD28 signalling in T cells: SH2/SH3 domains, protein-tyrosine and lipid kinases, Immunol. Today 15, 225–234.Google Scholar
  129. Samelson, L. E., Phillips, A. F., Luong, E. T. and Klausner, R. D. (1990) Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor, Proc. Natl Acad. Sci. USA 87, 4358–4362.PubMedGoogle Scholar
  130. Samelson, L. E. and Klausner, R. D. (1992) Tyrosine kinases and tyrosine-based activation motifs. Current research on activation via the T cell antigen receptor, J. Biol. Chem 267, 24913–24916.PubMedGoogle Scholar
  131. Sancho, J., Peter, M. E., Franco, R., Danielian, S., Kang, J. S., Fagard, R., Woods, J., Reed, J. C., Kamoun, M. and Terhorst, C. (1993) Coupling of GTP-binding to the T cell receptor (TCR) ç-chain with TCR-mediated signal transduction, J. Immunol 150, 3230–3242.PubMedGoogle Scholar
  132. Sarosi, G. A., Thomas, P. M., Egerton, M., Phillips, A. F., Kim, K. W., Bonvini, E. and Samelson, L. E. (1992) Characterization of the T cell antigen receptor-p60fy“ protein-tyrosine kinase association by chemical cross-linking, Int. Immunol 4, 1211–1217.PubMedGoogle Scholar
  133. Sasaki, Y., Asaoka, Y. and Nishizuka, Y. (1993) Potentiation of diacylglycerol-induced activation of protein kinase C by lysophospholipids. Subspecies difference, FEBS Lett. 320, 47–51.PubMedGoogle Scholar
  134. Schaap, D., van der Wal, J., van Blitterswijk, W. J., van der Bend, R. L. and Ploegh, H. L. (1993) Diacylglycerol kinase is phosphorylated in vivo upon stimulation of the epidermal growth factor receptor and serine/threonine kinases, including protein kinase C-e, Biochem. J 289, 875–881.PubMedGoogle Scholar
  135. Schaap, D., van der Wal, J., Howe, L. R., Marshall, C. J., van Blitterswijk, W. J. (1993a) A dominant-negative mutant of Raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21 ras, J. Biol. Chem 268, 20232–20236.PubMedGoogle Scholar
  136. Schieven, G. L., Kirihara, J. M., Burg, D. L., Geahlen, R. L. and Ledbetter, J. A. (1993) Tyrosine kinase is activated by oxidizing conditions that induce lymphocyte tyrosine phosphorylation and Ca“ signals, J. Biol. Chem 268, 16688–16692.Google Scholar
  137. Schlessinger, J. (1993) How receptor tyrosine kinases activate Ras, Trends Biochem. Sci 18, 273–275.PubMedGoogle Scholar
  138. Secrist, J. P., Karnitz, L., Abraham, R. T. (1991) T-cell antigen receptor ligation induces tyrosine phosphorylation of phospholipase C-y-1, J. Biol. Chem. 266, 12 135 —12139.Google Scholar
  139. Selbie, L. A., Schmitz-Peiffer, C., Sheng, Y. and Biden, T. J. (1993) Molecular cloning and characterization of PKC-iota, an atypical isoform of protein kinase C derived from insulin secreting cells, J. Biol. Chem. 268, 24296 — 24302.Google Scholar
  140. Shinomura, T., Asaoka, Y., Oka, M., Yoshida, K. and Nishizuka, Y. (1991) Synergistic action of diacylglycerol and unsaturated fatty acid for protein kinase C activation: its possible implications, Proc. Natl Acad. Sci. USA 88, 5149–5153.PubMedGoogle Scholar
  141. Siegel, J. N., Klausner, R. D., Rapp, U. R. and Samelson, L. E. (1990) T cell antigen receptor engagement stimulates c-raf phosphorylation and induces c-raf associated kinase activity via a protein kinase C-dependent pathway, J. Biol. Chem 265, 18472–18480.PubMedGoogle Scholar
  142. Siegel, J. N., June, C. H., Yamada, H., Rapp, U. R. and Samelson, L. E. (1993) Rapid activation of C-Raf-1 after stimulation of the T-cell receptor or the muscarinic receptor Type 1 in resting T cells, J. Immunol 151, 4116–4127.PubMedGoogle Scholar
  143. da Silva, A. J. and Rudd, C. E. (1993) A 72 kilodalton Fyn-related polypeptide (p72`n`-R) binds to the antigen-receptor-CD3 (TcR/CD3) complex, J. Biol. Chem 268, 16537–16543.Google Scholar
  144. da Silva, A. J., Janssen, O. and Rudd, C. E. (1993) T cell receptor /CD3p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T), J. Exp. Med 178, 2107–2113.PubMedGoogle Scholar
  145. Soltoff, S. P., Carpenter, C. L., Auger, K. R., Kapeller, R., Schaffhausen, B. and Cantley, L. C. (1992) Phosphatidylinositol 3-kinase and growth regulation, Cold Spring Harb. Symp. Quant. Biol 57, 75–80.PubMedGoogle Scholar
  146. Sommermeyer, H., Schwinzer, R., Kaever, V., Wessel, K., Schmidt, R. E., Behl, B., Wonigeit, K., Szamel, M. and Resch, K. (1989) Cholera toxin modulates the T cell antigen receptor/CD3 complex but not the CD2 molecule and inhibits signaling via both receptor structures in the human T cell lymphoma Jurkat, Eur. J. Immunol 19, 2387–2390.Google Scholar
  147. Stein, P. L., Lee, H. M., Rich, S. and Soriano, P. (1992) Fyn mutant mice display differential signaling in thymocytes and peripheral T cells, Cell 70, 741–750.PubMedGoogle Scholar
  148. Stewart, S. J., Cunningham, G. R., Strupp, J. A., House, FS, Kelley, LL., Henderson, G. S., Exton, J. H. and Bocchino, S. B. (1991) Activation of phospholipase D: a signaling system set in motion by perturbation of the T lymphocyte antigen receptor/CD3 complex, Cell. Regul. 2, 841– 850.Google Scholar
  149. Stover, D. R., Charbonneau, H., Tonks, N. K. and Walsh, K. A. (1991) Protein-tyrosine-phosphatase CD45 is phosphorylated transiently on tyrosine upon activation of Jurkat T cells, Proc. Natl Acad. Sci USA 88, 7704–7707.PubMedGoogle Scholar
  150. Straus, D. B. and Weiss, A. (1992) Genetic evidence for the involvement of the Ick tyrosine kinase in signal transduction through the T cell antigen receptor, Cell 70, 585–593.PubMedGoogle Scholar
  151. Szamel, M., Rehermann, B., Krebs, B., Kurrle, R. and Resch, K. (1989) Activation signals in human lymphocytes. Incorporation of polyunsaturated fatty acids into plasma membrane phospholipids regulates IL-2 synthesis via sustained activation of protein kinase C, J. Immunol 143, 2806–2813.PubMedGoogle Scholar
  152. Szamel, M., Kracht, M., Krebs, B., Huebner, U. and Resch, K. (1990) Activation signals in human lymphocytes, interleukin-2 synthesis and expression of high affinity interleukin-2 receptors require differential signalling for the activation of protein kinase C, Cell. hnmunol 126, 117–128.Google Scholar
  153. Szamel, M., Bartels, F. and Resch, K. (1993) Cyclosporin A inhibits T cell receptor-induced interleukin-2 synthesis of human T lymphocytes by selectively preventing a transmembrane signal transduction pathway leading to sustained activation of a protein kinase C isoenzyme, protein kinase C-ß, Eur. J. Immunol. 23, 3072–3081.Google Scholar
  154. Takeuchi, M., Kuramochi, S., Fusaki, N., Nada, S., Kawamura-Tsuzuku, J.. Matsuda, S., Semba, K., Toyoshima, K., Okada, M. and Yamamoto, T. (1993) Functional and physical interaction of protein-tyrosine kinases Fyn and Csk in the T-cell signaling system, J. Biol. Chem. 268, 27413 – 27419.PubMedGoogle Scholar
  155. Taniguchi, T., Kobayashi, T., Kondo, J., Takahashi, K., Nakamura, H., Susuki, J., Nagai, K., Yamada, T., Nakamura, S. and Yamamura, H. (1991)Molecular cloning of a porcine gene syk that encodes a 72-kDa protein, tyrosine kinase showing high susceptibility to proteolysis, J. Biol. Chem 266, 15790–15796.Google Scholar
  156. Thompson, N. T., Bonser, R. W. and Garland, L. G. (1991) Receptor-coupled phospholipase D and its inhibition, Trends Pharmacol. Sci 12, 404–408.PubMedGoogle Scholar
  157. Timson-Gauen, L. K., Kong, A. N.. Samelson, L. E. and Shaw, A. S. (1992) P59fY“ tyrosine kinase associates with multiple T-cell receptor subunits through its unique amino-terminal domain, Mol. Cell. Biol 12, 5438–5446.Google Scholar
  158. Towbridge, I. S. (1991) CD45: a prototype for transmembrane protein tyrosine phosphatases, J. Biol. Chem. 266, 23517–23620.Google Scholar
  159. Troppmair, J., Bruder, J. T., App, H., Cai, H., Liptak, L., Szeberenyi, J., Cooper, G. M. and Rapp, U. R. (1992)Rascontrols coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-raf protein serine kinases in the cytosol, Oncogene 7, 1867–1873.Google Scholar
  160. Tsutsumi, A., Kubo, M., Fujii, H., Freire., Moar., J.. Turck, C. W and Ransom, J. T. (1993) Regulation of protein kinase C isoform proteins in phorbol ester-stimulated Jurkat T lymphoma cells, J. Immunol 150, 1746–1754.Google Scholar
  161. Tsygankov, A. Y., Broker, B. M., Fargnoli, J., Ledbetter, J. A. and Bolen, J. B. (1992) Activation of tyrosine kinase p60fm following T cell antigen receptor cross-linking, J. Biol. Chem 267, 18259–18262.PubMedGoogle Scholar
  162. Veillette, A., Abraham, N., Caron, L. and Davidson, D. (1991) The lymphocyte-specific tyrosine protein kinase p561`k, Sem. Immunol. 3, 143–152.Google Scholar
  163. Vogel, L. B. and Fujita, D. J. (1993) The SH3 domain of p56’“ is involved in binding to phosphatidylinositol 3’-kinase from T lymphocytes, Mol. Cell. Biol 13, 7408–7417.PubMedGoogle Scholar
  164. Wange, R. L., Kong, A. N. and Samelson, L. E. (1992) A tyrosine-phosphorylated 70-kDa protein binds a photoaffinity analogue of ATP and associates with both the and CD3 components of the activated T cell antigen receptor, J. Biol. Chem 267, 11685–11688.PubMedGoogle Scholar
  165. Wange, R. L., Malek, S. N., Desiderio, S. and Samelson, L. E. (1993) Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor and CD3-epsilon from activated Jurkat T cells, J. Biol. Chem 268, 19797–19801.PubMedGoogle Scholar
  166. Warne, P. H., Viciana, P. R. and Downward, J. (1993) Direct interaction of ras and the amino-terminal region of Raf-1 in vitro, Nature 364, 352–355.Google Scholar
  167. Weber, J. R., Bell, G. M., Han, M. Y., Pawson, T. and Imboden, J. B. (1992) Association of the tyrosine kinase lck with phospholipase C-y 1 after stimulation of the T cell antigen receptor, J. Exp. Med. 176, 373–379.PubMedGoogle Scholar
  168. Wegener, A. M., Letourneur, F., Hoeveler, A., Brocker, T., Luton, E and Malissen, B. (1992) The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules, Cell 68, 83–95.PubMedGoogle Scholar
  169. Weiss, A. and Imboden, J. B. (1987) Cell surface molecules and early events in human T lymphocyte activation, Adv. Immunol 41, 1–38.PubMedGoogle Scholar
  170. Weiss, A., Koretzky, G., Schatzman, R. C. and Kadlecek, T. (1991) Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-y 1, Proc. Natl Acad. Sci. USA 88, 5484–5488.Google Scholar
  171. Weiss, A. and Littman, D. R. (1994) Signal transduction by lymphocyte antigen receptors, Cell 76, 263–274.PubMedGoogle Scholar
  172. Woodrow, M. A., Rayter, S., Downward, J. and Cantrell, D. A. (1993) A function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells, J. Immunol 150, 3853–3861.PubMedGoogle Scholar
  173. Woodrow, M., Clipstone, N. A. and Cantrell, D. (1993b) A and calcineurin synergize to regulate the nuclear factor of activated T cells, J. Exp. Med 178, 1517–1522.PubMedGoogle Scholar
  174. Wotton, D., Ways, D. K., Parker, P. J. and Owen, M. J. (1993) Activity of both Raf and Ras is necessary for activation of transcription of the human T cell receptor ß gene by protein kinase C, ras plays multiple roles, J. Biol. Chem 268, 17975–17982.PubMedGoogle Scholar
  175. Zhang, X. F., Settleman, J., Kyriakis, J. M., Takeuchi, Suzuki, E., Elledge, S. J., Marshall, M. S., Bruder, J. T., Rapp, U. R. and Avruch, J. (1993) Normal and oncogenic p21’s proteins bind to the amino-terminal regulatory domain of c-Raf-1, Nature 364, 308–313.PubMedGoogle Scholar

Copyright information

© FEBS 1995

Authors and Affiliations

  • Marta Szamel
    • 1
  • Klaus Resch
    • 1
  1. 1.Institute of Molecular PharmacologyMedical School HannoverHannoverGermany

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