Animals; Catalytic Domain; Extracellular Signal-Regulated MAP Kinases/metabolism; Humans; Intracellular Signaling Peptides and Proteins/genetics/metabolism; Isoenzymes/genetics/metabolism; Jurkat Cells/immunology/metabolism; Membrane Microdomains/metabolism; Mice; Phosphorylation; Protein Kinase C/genetics/metabolism; Protein Tyrosine Phosphatases/genetics/metabolism; Protein Tyrosine Phosphatases, Non-Receptor; Receptors, Antigen, T-Cell/genetics/metabolism; Serine/metabolism; Signal Transduction; T-Lymphocytes/immunology/metabolism; Transgenes
Abstract :
[en] Protein kinase C theta (PKC theta) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic protein tyrosine phosphatase (HePTP) also accumulates in the immune synapse in a PKC theta-dependent manner upon antigen recognition by T cells and is phosphorylated by PKC theta at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC theta-/- mice. In intact T cells, HePTP-S225A enhanced T-cell receptor (TCR)-induced NFAT/AP-1 transactivation, while the acidic substitution mutant was as efficient as wild-type HePTP. We conclude that HePTP is phosphorylated in the immune synapse by PKC theta and thereby targeted to lipid rafts to temper TCR signaling. This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling.
Adachi, M., M. Sekiya, M. Isobe, Y. Kumura, Z. Ogita, Y. Hinoda, K. Imai, and A. Yachi. 1992. Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP. Biochem. Biophys. Res. Commun. 186:1607-1615.
Alblas, J., R. Slager-Davidov, P. H. Steenbergh, J. S. Sussenbach, and B. van den Burg. 1998. The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells. Oncogene 16:131-139.
Alonso, A., S. Rahmouni, S. Williams, M. van Stipdonk, L. Jaroszewski, A. Godzik, R. T. Abraham, S. P. Schoenberger, and T. Mustelin. 2003. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat. Immunol. 4:44-48.
Alonso, A., J. Sasin, N. Bottini, I. Friedberg, I. Friedberg, A. Osterman, A. Godzik, T. Hunter, J. E. Dixon, and T. Mustelin. 2004. Protein tyrosine phosphatases in the human genome. Cell 117:699-711.
Baier, G., D. Telford, L. Giampa, K. M. Coggeshall, G. Baier-Bitterlich, N. Isakov, and A. Altman. 1993. Molecular cloning and characterization of PKCθ, a human novel member of the PKC gene family expressed predominately in hematopoietic cells. J. Biol. Chem. 268:4997-5004.
Baier-Bitterlich, G., F. Uberall, B. Bauer, F. Fresser, H. Watcher, H. Grunicke, G. Utermann, A. Altman, and G. Baier. 1996. Protein kinase C-θ isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes. Mol. Cell. Biol. 16:1842-1850.
Bi, K., Y. Tanaka, N. Courdonniere, S. Hong, K. Sugie, M, J. B. van Stipdonk, and A. Altman. 2001. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nat. Immunol. 2:556-563.
Chau, A. S.-S., and E. K. Shibuya. 1999. Inactivation of p42 mitogen-activated protein kinase is required for exit from M-phase after cyclin destruction. J. Biol. Chem. 274:32085-32090.
Coudronniere, N., M. Villaba, N. Englund, and A. Altman. 2000. NF-κB activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-θ. Proc. Natl. Acad. Sci. USA 97:3394-3399.
Ghaffari-Tabrizi, N., B. Bauer, A. Villunger, G. Baier-Bitterlich, A. Altman, G. Utermann, F. Uberall, and G. Baier. 1999. Protein kinase C θ, a selective upstream regulator of JNK/SAPK and IL-2 promoter activation in Jurkat T cells. Eur. J. Immunol 29:132-142.
Gronda, M., S. Arab, B. Iafrate, H. Suzuki, and B. Zanke. 2001. Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol. Cell. Biol. 21:6851-6858.
Li, Y., H. Junru, R. Vita, B. Sun, H. Tabata, and A. Altman. 2004. SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway. EMBO J. 23:1112-1122.
Luo, K., T. R. Hurley, and B. M. Sefton. 1990. Transfer of proteins to membranes facilitates both cyanogen bromide cleavage and two-dimensional proteolytic mapping. Oncogene 5:921-923.
Marshall, C. J. 1995. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179-185.
Monks, C. R., H. Kupfer, I. Tamir, A. Barlow, and A. Kupfer. 1997. Selective modulation of protein kinase C-theta during T cell activation. Nature 385: 83-86.
Mustelin, T., T. Vang, and N. Bottini. 2005. Protein tyrosine phosphatases and the immune response. Nat. Rev. Immunol. 5:43-57.
Nika, K., H. Huynh, S. Williams, S. Paul, N. Bottini, K. Taskén, P. J. Lombroso, and T. Mustelin. 2004. Haematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T cells: dynamics and subcellular location. Biochem. J. 378:335-342.
Oh-hora, M., M. Ogata, Y. Mori, M. Adachi, K. Imai, A. Kosugi, and T. Hamaoka. 1999. Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. J. Immunol. 163:1282-1288.
Osada, S., K. Mizuno, T. C. Saido, K. Suzuki, T. Kuroki, and S. Ohno. 1992. A new member of the protein kinase C family, nPKCθ, predominantly expressed in skeletal muscle. Mol. Cell. Biol. 12:3930-3938.
Pfeifhofer, C., K. Kofler, T. Cruber, N. Ghaffari-Tabrizi, C. Lutz, K. Maly, M. Leitges, and G. Baier. 2003. Protein kinase Cθ affects Ca 2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197:1525-1535.
Rahmouni, S., T. Vang, A. Alonso, S. Williams, M. van Stipdonk, C. Soncini, M. Moutschen, S. P. Schoenberger, and T. Mustelin. 2005. Removal of C-terminal Src kinase from the immune synapse by a new binding protein. Mol. Cell. Biol. 25:2227-2241.
Sablina, A. A., P. M. Chumakov, A. J. Levine, and B. P. Kopnin. 2001. p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling. Oncogene 20:899-909.
Saxena, M., S. Williams, J, Brockdorff, J. Gilman, and T. Mustelin. 1999. Inhibition of T cell signaling by MAP kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 274:11693-11700.
Saxena, M., S. Williams, J. Gilman, and T. Mustelin. 1998. Negative regulation of T cell antigen receptor signaling by hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 273:15340-15344.
Saxena, M., S. Williams, K. Taskén, and T. Mustelin. 1999. Crosstalk between cAMP-dependent kinase and MAP kinase through hematopoietic protein tyrosine phosphatase (HePTP). Nat. Cell Biol. 1:305-311.
Sedwick, C. E., and A. Altman. 2004. Perspectives on PKCθ in T cell activation. Mol. Immunol. 41:675-686.
Serrano, M., A. W. Lin, M. E. McCurrach, D. Beach, and S. W. Lowe. 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593-602.
Sun, Z., C. W. Arendt, W. Ellmeier, E. M. Schaeffer, M. J. Sunshine, L. Gandhi, J. Annes, D. Petrzilka, A. Kupfer, P. L. Schwartzberg, and D. R. Littman. 2000. PKC-θ is required for TCR-induced NF-B activation in mature but not immature T lymphocytes. Nature 404:402-407.
Tang, D., D. Wu, A. Hirao, J. M. Lahti, L. Liu, B. Mazza, V. J. Kidd, T. W. Mak, and A. J. Ingram. 2002. ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J. Biol. Chem. 277: 12710-12717.
Villalba, M., K. Bi, H. Junru, Y. Altman, P. Bushway, E. Reits, J. Neefjes, G. Baier, R. T. Abraham, and A. Altman. 2002. Translocation of PKC-θ in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. J. Cell Biol. 157:253-263.
Wang, W., J. X. Chen, R. Liao, Q. Deng, J. J. Zhou, S. Huang, and P. Sun. 2002. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol. Cell. Biol. 22:3389-3403.
Zanke, B., H. Suzuki, K. Kishihara, L. Mizzen, M. Minden, A. Pawson, and T. W. Mak. 1992. Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase). Eur. J. Immunol. 22:235-239.
Zhang, W., R. P. Trible, and L. E. Samelson. 1998. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9:239-246.
