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*
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, and
Departments of Microbiology, Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada
CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen-activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF complexes, an event critical for Ag receptor-triggered T cell activation. Here, we show that TCR/CD28 costimulation synergistically induces Rac-1 GDP/GTP exchange. Our findings, obtained by using ZAP-70-negative Jurkat T cells, indicate that CD28 costimulation augments TCR-mediated T cell activation by increasing the ZAP-70-mediated Tyr phosphorylation of Vav. This event regulates the Rac-1-associated GTP/GDP exchange activity of Vav and downstream pathway(s) leading to PAK-1 and p38 MAPK activation. CD28 amplifies TCR-induced ZAP-70 activity and association of Vav with ZAP-70 and linker for activation of T cells (LAT). These results favor a model in which ZAP-70 regulates the intersection of the TCR and CD28 signaling pathways, which elicits the coupling of TCR and CD28 to the Rac-1, PAK-1, and p38 MAPK effector molecules.
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S. L. Moores, L. M. Selfors, J. Fredericks, T. Breit, K. Fujikawa, F. W. Alt, J. S. Brugge, and W. Swat Vav Family Proteins Couple to Diverse Cell Surface Receptors Mol. Cell. Biol., September 1, 2000; 20(17): 6364 - 6373. [Abstract] [Full Text]
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R. Visconti, M. Gadina, M. Chiariello, E. H. Chen, L. F. Stancato, J. S. Gutkind, and J. J. O'Shea Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity Blood, September 1, 2000; 96(5): 1844 - 1852. [Abstract] [Full Text] [PDF]
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B. Lucas and R. N. Germain Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement J. Immunol., August 15, 2000; 165(4): 1889 - 1895. [Abstract] [Full Text] [PDF]
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D. A. Witherden, R. Boismenu, and W. L. Havran CD81 and CD28 Costimulate T Cells Through Distinct Pathways J. Immunol., August 15, 2000; 165(4): 1902 - 1909. [Abstract] [Full Text] [PDF]
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S. P. Hehner, M. Li-Weber, M. Giaisi, W. Droge, P. H. Krammer, and M. L. Schmitz Vav Synergizes with Protein Kinase C{Theta} to Mediate IL-4 Gene Expression in Response to CD28 Costimulation in T Cells J. Immunol., April 1, 2000; 164(7): 3829 - 3836. [Abstract] [Full Text] [PDF]
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X. R. Bustelo Regulatory and Signaling Properties of the Vav Family Mol. Cell. Biol., March 1, 2000; 20(5): 1461 - 1477. [Full Text]
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K. V. Salojin, J. Zhang, C. Meagher, and T. L. Delovitch ZAP-70 Is Essential for the T Cell Antigen Receptor-induced Plasma Membrane Targeting of SOS and Vav in T Cells J. Biol. Chem., February 25, 2000; 275(8): 5966 - 5975. [Abstract] [Full Text] [PDF]
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S. Uddin, F. Lekmine, N. Sharma, B. Majchrzak, I. Mayer, P. R. Young, G. M. Bokoch, E. N. Fish, and L. C. Platanias The Rac1/p38 Mitogen-activated Protein Kinase Pathway Is Required for Interferon alpha -dependent Transcriptional Activation but Not Serine Phosphorylation of Stat Proteins J. Biol. Chem., September 1, 2000; 275(36): 27634 - 27640. [Abstract] [Full Text] [PDF]
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Y. Alsayed, S. Uddin, N. Mahmud, F. Lekmine, D. V. Kalvakolanu, S. Minucci, G. Bokoch, and L. C. Platanias Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid J. Biol. Chem., February 2, 2001; 276(6): 4012 - 4019. [Abstract] [Full Text] [PDF]
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S.-H. Lee, M. Eom, S. J. Lee, S. Kim, H.-J. Park, and D. Park beta Pix-enhanced p38 Activation by Cdc42/Rac/PAK/MKK3/6-mediated Pathway. IMPLICATION IN THE REGULATION OF MEMBRANE RUFFLING J. Biol. Chem., June 29, 2001; 276(27): 25066 - 25072. [Abstract] [Full Text] [PDF]
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A. Moller, O. Dienz, S. P. Hehner, W. Droge, and M. L. Schmitz Protein Kinase C theta Cooperates with Vav1 to Induce JNK Activity in T-cells J. Biol. Chem., June 1, 2001; 276(23): 20022 - 20028. [Abstract] [Full Text] [PDF]
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I. A. Mayer, A. Verma, I. M. Grumbach, S. Uddin, F. Lekmine, F. Ravandi, B. Majchrzak, S. Fujita, E. N. Fish, and L. C. Platanias The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-alpha in BCR-ABL-expressing Cells J. Biol. Chem., July 20, 2001; 276(30): 28570 - 28577. [Abstract] [Full Text] [PDF]
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J. Glassford, M. Holman, L. Banerji, E. Clayton, G. G. B. Klaus, M. Turner, and E. W.-F. Lam Vav Is Required for Cyclin D2 Induction and Proliferation of Mouse B Lymphocytes Activated via the Antigen Receptor J. Biol. Chem., October 26, 2001; 276(44): 41040 - 41048. [Abstract] [Full Text] [PDF]
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J. C. Patel, A. Hall, and E. Caron Vav Regulates Activation of Rac but Not Cdc42 during Fcgamma R-mediated Phagocytosis Mol. Biol. Cell, April 1, 2002; 13(4): 1215 - 1226. [Abstract] [Full Text] [PDF]
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