Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 + T Cells
10.1126/science.271.5253.1272
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

T cells activated by antigen receptor stimulation in the absence of accessory cell-derived costimulatory signals lose the capacity to synthesize the growth factor interleukin-2 (IL-2), a state called clonal anergy. An analysis of CD3- and CD28-induced signal transduction revealed reduced ERK and JNK enzyme activities in murine anergic T cells. The amounts of ERK and JNK proteins were unchanged, and the kinases could be fully activated in the presence of phorbol 12-myristate 13-acetate. Dephosphorylation of the calcineurin substrate NFATp (preexisting nuclear factor of activated T cells) also remained inducible. These results suggest that a specific block in the activation of ERK and JNK contributes to defective IL-2 production in clonal anergy.

Bibliography

Li, W., Whaley, C. D., Mondino, A., & Mueller, D. L. (1996). Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 + T Cells. Science, 271(5253), 1272–1276.

Authors 4
  1. Wei Li (first)
  2. Carmella D. Whaley (additional)
  3. Anna Mondino (additional)
  4. Daniel L. Mueller (additional)
References 49 Referenced 344
  1. 10.1126/science.169.3950.1042
  2. CHAO TSO, ACTIVATION OF MAP KINASES BY CALCIUM-DEPENDENT AND CALCIUM-INDEPENDENT PATHWAYS - STIMULATION BY THAPSIGARGIN AND EPIDERMAL GROWTH-FACTOR, JOURNAL OF BIOLOGICAL CHEMISTRY 267, 19876 (1992). (10.1016/S0021-9258(19)88637-4) / JOURNAL OF BIOLOGICAL CHEMISTRY / ACTIVATION OF MAP KINASES BY CALCIUM-DEPENDENT AND CALCIUM-INDEPENDENT PATHWAYS - STIMULATION BY THAPSIGARGIN AND EPIDERMAL GROWTH-FACTOR by CHAO TSO (1992)
  3. CHO A. E., ALTERED PROTEIN-TYROSINE PHOSPHORYLATION IN ANERGIC TH1 CELLS, JOURNAL OF IMMUNOLOGY 151, 20 (1993). (10.4049/jimmunol.151.1.20) / JOURNAL OF IMMUNOLOGY / ALTERED PROTEIN-TYROSINE PHOSPHORYLATION IN ANERGIC TH1 CELLS by CHO A. E. (1993)
  4. 10.1016/S0092-8674(05)80018-2
  5. 10.1126/science.1411546
  6. 10.1126/science.1326789
  7. DERIJARD B, JNK1 - A PROTEIN-KINASE STIMULATED BY UV-LIGHT AND HA-RAS THAT BINDS AND PHOSPHORYLATES THE C-JUN ACTIVATION DOMAIN, CELL 76, 1025 (1994). (10.1016/0092-8674(94)90380-8) / CELL / JNK1 - A PROTEIN-KINASE STIMULATED BY UV-LIGHT AND HA-RAS THAT BINDS AND PHOSPHORYLATES THE C-JUN ACTIVATION DOMAIN by DERIJARD B (1994)
  8. DOWNWARD J, STIMULATION OF P21RAS UPON T-CELL ACTIVATION, NATURE 346, 719 (1990). (10.1038/346719a0) / NATURE / STIMULATION OF P21RAS UPON T-CELL ACTIVATION by DOWNWARD J (1990)
  9. FIERING S, SINGLE CELL ASSAY OF A TRANSCRIPTION FACTOR REVEALS A THRESHOLD IN TRANSCRIPTION ACTIVATED BY SIGNALS EMANATING FROM THE T-CELL ANTIGEN RECEPTOR, GENES & DEVELOPMENT 4, 1823 (1990). (10.1101/gad.4.10.1823) / GENES & DEVELOPMENT / SINGLE CELL ASSAY OF A TRANSCRIPTION FACTOR REVEALS A THRESHOLD IN TRANSCRIPTION ACTIVATED BY SIGNALS EMANATING FROM THE T-CELL ANTIGEN RECEPTOR by FIERING S (1990)
  10. 10.1126/science.7694363
  11. GAJEWSKI F. T., ANERGIC T-LYMPHOCYTE CLONES HAVE ALTERED INOSITOL PHOSPHATE, CALCIUM, AND TYROSINE KINASE SIGNALING PATHWAYS, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91, 38 (1994). (10.1073/pnas.91.1.38) / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA / ANERGIC T-LYMPHOCYTE CLONES HAVE ALTERED INOSITOL PHOSPHATE, CALCIUM, AND TYROSINE KINASE SIGNALING PATHWAYS by GAJEWSKI F. T. (1994)
  12. GIMMI D. C., B-CELL SURFACE ANTIGEN-B7 PROVIDES A COSTIMULATORY SIGNAL THAT INDUCES T-CELLS TO PROLIFERATE AND SECRETE INTERLEUKIN-2, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 88, 6575 (1991). (10.1073/pnas.88.15.6575) / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA / B-CELL SURFACE ANTIGEN-B7 PROVIDES A COSTIMULATORY SIGNAL THAT INDUCES T-CELLS TO PROLIFERATE AND SECRETE INTERLEUKIN-2 by GIMMI D. C. (1991)
  13. HARDING A. F., CD28-MEDIATED SIGNALING CO-STIMULATES MURINE T-CELLS AND PREVENTS INDUCTION OF ANERGY IN T-CELL CLONES, NATURE 356, 607 (1992). (10.1038/356607a0) / NATURE / CD28-MEDIATED SIGNALING CO-STIMULATES MURINE T-CELLS AND PREVENTS INDUCTION OF ANERGY IN T-CELL CLONES by HARDING A. F. (1992)
  14. HECHT T. T., THE RELATIONSHIP BETWEEN IMMUNE INTERFERON-PRODUCTION AND PROLIFERATION IN ANTIGEN-SPECIFIC, MHC-RESTRICTED T-CELL LINES AND CLONES, JOURNAL OF IMMUNOLOGY 131, 1049 (1983). (10.4049/jimmunol.131.3.1049) / JOURNAL OF IMMUNOLOGY / THE RELATIONSHIP BETWEEN IMMUNE INTERFERON-PRODUCTION AND PROLIFERATION IN ANTIGEN-SPECIFIC, MHC-RESTRICTED T-CELL LINES AND CLONES by HECHT T. T. (1983)
  15. HIBI M, IDENTIFICATION OF AN ONCOPROTEIN-RESPONSIVE AND UV-RESPONSIVE PROTEIN-KINASE THAT BINDS AND POTENTIATES THE C-JUN ACTIVATION DOMAIN, GENES & DEVELOPMENT 7, 2135 (1993). (10.1101/gad.7.11.2135) / GENES & DEVELOPMENT / IDENTIFICATION OF AN ONCOPROTEIN-RESPONSIVE AND UV-RESPONSIVE PROTEIN-KINASE THAT BINDS AND POTENTIATES THE C-JUN ACTIVATION DOMAIN by HIBI M (1993)
  16. IZQUIERDO M, IMMUNOL TODAY 16, 159 (1995). (10.1016/0167-5699(95)80134-0) / IMMUNOL TODAY by IZQUIERDO M (1995)
  17. IZQUIERDO M, P21(RAS) COUPLES THE T-CELL ANTIGEN RECEPTOR TO EXTRACELLULAR SIGNAL-REGULATED KINASE-2 IN T-LYMPHOCYTES, JOURNAL OF EXPERIMENTAL MEDICINE 178, 1199 (1993). (10.1084/jem.178.4.1199) / JOURNAL OF EXPERIMENTAL MEDICINE / P21(RAS) COUPLES THE T-CELL ANTIGEN RECEPTOR TO EXTRACELLULAR SIGNAL-REGULATED KINASE-2 IN T-LYMPHOCYTES by IZQUIERDO M (1993)
  18. JAIN N. J., ANALYSIS OF THE PREEXISTING AND NUCLEAR FORMS OF NUCLEAR FACTOR OF ACTIVATED T-CELLS, JOURNAL OF IMMUNOLOGY 151, 837 (1993). (10.4049/jimmunol.151.2.837) / JOURNAL OF IMMUNOLOGY / ANALYSIS OF THE PREEXISTING AND NUCLEAR FORMS OF NUCLEAR FACTOR OF ACTIVATED T-CELLS by JAIN N. J. (1993)
  19. JAIN N. J., THE T-CELL TRANSCRIPTION FACTOR NFAT(P) IS A SUBSTRATE FOR CALCINEURIN AND INTERACTS WITH FOS AND JUN, NATURE 365, 352 (1993). (10.1038/365352a0) / NATURE / THE T-CELL TRANSCRIPTION FACTOR NFAT(P) IS A SUBSTRATE FOR CALCINEURIN AND INTERACTS WITH FOS AND JUN by JAIN N. J. (1993)
  20. JENKINS K. M., ANTIGEN PRESENTATION BY CHEMICALLY MODIFIED SPLENOCYTES INDUCES ANTIGEN-SPECIFIC T-CELL UNRESPONSIVENESS INVITRO AND INVIVO, JOURNAL OF EXPERIMENTAL MEDICINE 165, 302 (1987). (10.1084/jem.165.2.302) / JOURNAL OF EXPERIMENTAL MEDICINE / ANTIGEN PRESENTATION BY CHEMICALLY MODIFIED SPLENOCYTES INDUCES ANTIGEN-SPECIFIC T-CELL UNRESPONSIVENESS INVITRO AND INVIVO by JENKINS K. M. (1987)
  21. JENKINS K. M., INHIBITION OF ANTIGEN-SPECIFIC PROLIFERATION OF TYPE-1 MURINE T-CELL CLONES AFTER STIMULATION WITH IMMOBILIZED ANTI-CD3 MONOCLONAL-ANTIBODY, JOURNAL OF IMMUNOLOGY 144, 16 (1990). (10.4049/jimmunol.144.1.16) / JOURNAL OF IMMUNOLOGY / INHIBITION OF ANTIGEN-SPECIFIC PROLIFERATION OF TYPE-1 MURINE T-CELL CLONES AFTER STIMULATION WITH IMMOBILIZED ANTI-CD3 MONOCLONAL-ANTIBODY by JENKINS K. M. (1990)
  22. JENKINS K. M., MOLECULAR EVENTS IN THE INDUCTION OF A NONRESPONSIVE STATE IN INTERLEUKIN 2-PRODUCING HELPER LYMPHOCYTE-T CLONES, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 84, 5409 (1987). (10.1073/pnas.84.15.5409) / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA / MOLECULAR EVENTS IN THE INDUCTION OF A NONRESPONSIVE STATE IN INTERLEUKIN 2-PRODUCING HELPER LYMPHOCYTE-T CLONES by JENKINS K. M. (1987)
  23. 10.1126/science.257.5073.1134
  24. 10.1126/science.7618083
  25. LEO O, IDENTIFICATION OF A MONOCLONAL-ANTIBODY SPECIFIC FOR A MURINE T3 POLYPEPTIDE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 84, 1374 (1987). (10.1073/pnas.84.5.1374) / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA / IDENTIFICATION OF A MONOCLONAL-ANTIBODY SPECIFIC FOR A MURINE T3 POLYPEPTIDE by LEO O (1987)
  26. LI W unpublished data.
  27. MARAIS R, THE SRF ACCESSORY PROTEIN ELK-1 CONTAINS A GROWTH FACTOR-REGULATED TRANSCRIPTIONAL ACTIVATION DOMAIN, CELL 73, 381 (1993). (10.1016/0092-8674(93)90237-K) / CELL / THE SRF ACCESSORY PROTEIN ELK-1 CONTAINS A GROWTH FACTOR-REGULATED TRANSCRIPTIONAL ACTIVATION DOMAIN by MARAIS R (1993)
  28. MCCAFFREY G. P., NF-ATP, A LYMPHOCYTE-T DNA-BINDING PROTEIN THAT IS A TARGET FOR CALCINEURIN AND IMMUNOSUPPRESSIVE DRUGS, JOURNAL OF BIOLOGICAL CHEMISTRY 268, 3747 (1993). (10.1016/S0021-9258(18)53757-1) / JOURNAL OF BIOLOGICAL CHEMISTRY / NF-ATP, A LYMPHOCYTE-T DNA-BINDING PROTEIN THAT IS A TARGET FOR CALCINEURIN AND IMMUNOSUPPRESSIVE DRUGS by MCCAFFREY G. P. (1993)
  29. 10.1016/S0092-8674(05)80019-4
  30. 10.1126/science.7992057
  31. MONDINO A unpublished data.
  32. 10.1126/science.8503013
  33. MUELLER L. D., CLONAL EXPANSION VERSUS FUNCTIONAL CLONAL INACTIVATION - A COSTIMULATORY SIGNALING PATHWAY DETERMINES THE OUTCOME OF T-CELL ANTIGEN RECEPTOR OCCUPANCY, ANNUAL REVIEW OF IMMUNOLOGY 7, 445 (1989). (10.1146/annurev.iy.07.040189.002305) / ANNUAL REVIEW OF IMMUNOLOGY / CLONAL EXPANSION VERSUS FUNCTIONAL CLONAL INACTIVATION - A COSTIMULATORY SIGNALING PATHWAY DETERMINES THE OUTCOME OF T-CELL ANTIGEN RECEPTOR OCCUPANCY by MUELLER L. D. (1989)
  34. MUELLER L. D., MOLECULAR MECHANISMS UNDERLYING FUNCTIONAL T-CELL UNRESPONSIVENESS, CURRENT OPINION IN IMMUNOLOGY 7, 375 (1995). (10.1016/0952-7915(95)80113-8) / CURRENT OPINION IN IMMUNOLOGY / MOLECULAR MECHANISMS UNDERLYING FUNCTIONAL T-CELL UNRESPONSIVENESS by MUELLER L. D. (1995)
  35. MUELLER L. D., AN ACCESSORY CELL-DERIVED COSTIMULATORY SIGNAL ACTS INDEPENDENTLY OF PROTEIN KINASE-C ACTIVATION TO ALLOW T-CELL PROLIFERATION AND PREVENT THE INDUCTION OF UNRESPONSIVENESS, JOURNAL OF IMMUNOLOGY 142, 2617 (1989). (10.4049/jimmunol.142.8.2617) / JOURNAL OF IMMUNOLOGY / AN ACCESSORY CELL-DERIVED COSTIMULATORY SIGNAL ACTS INDEPENDENTLY OF PROTEIN KINASE-C ACTIVATION TO ALLOW T-CELL PROLIFERATION AND PREVENT THE INDUCTION OF UNRESPONSIVENESS by MUELLER L. D. (1989)
  36. MUELLER L. D., AN INTRACELLULAR CALCIUM INCREASE AND PROTEIN KINASE-C ACTIVATION FAIL TO INITIATE T-CELL PROLIFERATION IN THE ABSENCE OF A COSTIMULATORY SIGNAL, JOURNAL OF IMMUNOLOGY 144, 3701 (1990). (10.4049/jimmunol.144.10.3701) / JOURNAL OF IMMUNOLOGY / AN INTRACELLULAR CALCIUM INCREASE AND PROTEIN KINASE-C ACTIVATION FAIL TO INITIATE T-CELL PROLIFERATION IN THE ABSENCE OF A COSTIMULATORY SIGNAL by MUELLER L. D. (1990)
  37. MUELLER L. D., CLONAL ANERGY BLOCKS THE RESPONSE TO IL-4, AS WELL AS THE PRODUCTION OF IL-2, IN DUAL-PRODUCING T-HELPER CELL CLONES, JOURNAL OF IMMUNOLOGY 147, 4118 (1991). (10.4049/jimmunol.147.12.4118) / JOURNAL OF IMMUNOLOGY / CLONAL ANERGY BLOCKS THE RESPONSE TO IL-4, AS WELL AS THE PRODUCTION OF IL-2, IN DUAL-PRODUCING T-HELPER CELL CLONES by MUELLER L. D. (1991)
  38. NEL E. A., LIGATION OF THE T-CELL ANTIGEN RECEPTOR (TCR) INDUCES ASSOCIATION OF HSOS1, ZAP-70, PHOSPHOLIPASE C-GAMMA-1, AND OTHER PHOSPHOPROTEINS WITH GRB2 AND THE ZETA-CHAIN OF THE TCR, JOURNAL OF BIOLOGICAL CHEMISTRY 270, 18428 (1995). (10.1074/jbc.270.31.18428) / JOURNAL OF BIOLOGICAL CHEMISTRY / LIGATION OF THE T-CELL ANTIGEN RECEPTOR (TCR) INDUCES ASSOCIATION OF HSOS1, ZAP-70, PHOSPHOLIPASE C-GAMMA-1, AND OTHER PHOSPHOPROTEINS WITH GRB2 AND THE ZETA-CHAIN OF THE TCR by NEL E. A. (1995)
  39. OWAKI H, EXTRACELLULAR SIGNAL-REGULATED KINASES IN T-CELLS - CHARACTERIZATION OF HUMAN ERK1 AND ERK2 CDNAS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 182, 1416 (1992). (10.1016/0006-291X(92)91891-S) / BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS / EXTRACELLULAR SIGNAL-REGULATED KINASES IN T-CELLS - CHARACTERIZATION OF HUMAN ERK1 AND ERK2 CDNAS by OWAKI H (1992)
  40. QUILL H, ANERGIC TH1-CELLS EXPRESS ALTERED LEVELS OF THE PROTEIN TYROSINE KINASES P56(LCK) AND P59(FYN1), JOURNAL OF IMMUNOLOGY 149, 2887 (1992). (10.4049/jimmunol.149.9.2887) / JOURNAL OF IMMUNOLOGY / ANERGIC TH1-CELLS EXPRESS ALTERED LEVELS OF THE PROTEIN TYROSINE KINASES P56(LCK) AND P59(FYN1) by QUILL H (1992)
  41. SAMBROOK J, MOL CLONING (1989). / MOL CLONING by SAMBROOK J (1989)
  42. SANCHEZ I, ROLE OF SAPK/ERK KINASE-1 IN THE STRESS-ACTIVATED PATHWAY REGULATING TRANSCRIPTION FACTOR C-JUN, NATURE 372, 794 (1994). (10.1038/372794a0) / NATURE / ROLE OF SAPK/ERK KINASE-1 IN THE STRESS-ACTIVATED PATHWAY REGULATING TRANSCRIPTION FACTOR C-JUN by SANCHEZ I (1994)
  43. SMITH B. D., SINGLE-STEP PURIFICATION OF POLYPEPTIDES EXPRESSED IN ESCHERICHIA-COLI AS FUSIONS WITH GLUTATHIONE S-TRANSFERASE, GENE 67, 31 (1988). (10.1016/0378-1119(88)90005-4) / GENE / SINGLE-STEP PURIFICATION OF POLYPEPTIDES EXPRESSED IN ESCHERICHIA-COLI AS FUSIONS WITH GLUTATHIONE S-TRANSFERASE by SMITH B. D. (1988)
  44. SU B, JNK IS INVOLVED IN SIGNAL INTEGRATION DURING COSTIMULATION OF T-LYMPHOCYTES, CELL 77, 727 (1994). (10.1016/0092-8674(94)90056-6) / CELL / JNK IS INVOLVED IN SIGNAL INTEGRATION DURING COSTIMULATION OF T-LYMPHOCYTES by SU B (1994)
  45. WARD Y, CONTROL OF MAP KINASE ACTIVATION BY THE MITOGEN-INDUCED THREONINE/TYROSINE PHOSPHATASE PAC1, NATURE 367, 651 (1994). (10.1038/367651a0) / NATURE / CONTROL OF MAP KINASE ACTIVATION BY THE MITOGEN-INDUCED THREONINE/TYROSINE PHOSPHATASE PAC1 by WARD Y (1994)
  46. WHALEY D. C. unpublished data.
  47. WHITEHURST E. C., EXTRACELLULAR SIGNAL-REGULATED KINASES IN T-CELLS - ANTI-CD3 AND 4-BETA-PHORBOL 12-MYRISTATE 13-ACETATE-INDUCED PHOSPHORYLATION AND ACTIVATION, JOURNAL OF IMMUNOLOGY 148, 3230 (1992). (10.4049/jimmunol.148.10.3230) / JOURNAL OF IMMUNOLOGY / EXTRACELLULAR SIGNAL-REGULATED KINASES IN T-CELLS - ANTI-CD3 AND 4-BETA-PHORBOL 12-MYRISTATE 13-ACETATE-INDUCED PHOSPHORYLATION AND ACTIVATION by WHITEHURST E. C. (1992)
  48. 10.1126/science.7618106
  49. YAN H. M., ACTIVATION OF STRESS-ACTIVATED PROTEIN-KINASE BY MEKK1 PHOSPHORYLATION OF ITS ACTIVATOR SEK1, NATURE 372, 798 (1994). (10.1038/372798a0) / NATURE / ACTIVATION OF STRESS-ACTIVATED PROTEIN-KINASE BY MEKK1 PHOSPHORYLATION OF ITS ACTIVATOR SEK1 by YAN H. M. (1994)
Dates
Type When
Created 18 years, 10 months ago (Oct. 27, 2006, 2:30 p.m.)
Deposited 1 year, 7 months ago (Jan. 12, 2024, 4:32 p.m.)
Indexed 1 month ago (July 30, 2025, 8:25 p.m.)
Issued 29 years, 6 months ago (March 1, 1996)
Published 29 years, 6 months ago (March 1, 1996)
Published Print 29 years, 6 months ago (March 1, 1996)
Funders 0

None

@article{Li_1996, title={Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 + T Cells}, volume={271}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.271.5253.1272}, DOI={10.1126/science.271.5253.1272}, number={5253}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Li, Wei and Whaley, Carmella D. and Mondino, Anna and Mueller, Daniel L.}, year={1996}, month=mar, pages={1272–1276} }