title: Dual role of ERK5 in the regulation of T cell receptor expression at the T cell surface.
abstract: Regulation of the levels of the TCR/CD3 complex at the cell surface is critical to proper T cell development and mature T cell activation. We provide evidence that the MAPK ERK5 regulates the surface expression of the TCR/CD3 complex by controlling the degradation of the CD3ζ chain and the recovery of the complex after anti-CD3ε stimulation. ERK5 knockdown led to TCR/CD3 up-regulation at the cell surface and increased amounts of the CD3ζ chain. Inhibition of the MEK5-dependent phosphorylation status of the kinase domain of ERK5 in human T CD4(+) cells reduced CD3ζ ubiquitination and degradation, limiting TCR/CD3 down-regulation in anti-CD3-stimulated cells. Moreover, TCR/CD3 recovery at the cell surface, after anti-CD3ε treatment, is impaired by ERK5 knockdown or pharmacological inhibition of autophosphorylation in the ERK5 C-terminal region. ERK5 loss in thymocytes augmented cellular CD3ζ and increased cell surface levels of TCR/CD3 on CD4(+)CD8(+) thymocytes. This correlated with enhanced generation of CD4(+)CD8(-)CD25(+) thymocytes. Our findings define ERK5 as a novel kinase that modulates the levels of TCR/CD3 at the cell surface by promoting CD3ζ degradation and TCR/CD3 recovery after TCR stimulation.
authors: *Celltec-UB, Department of Cell Biology, and Department of Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; and University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom.
authors: Xavier
authors: X
authors: Rovira-Clavé
authors: *Celltec-UB, Department of Cell Biology, and Department of Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; and University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom.
authors: Maria
authors: M
authors: Angulo-Ibáñez
authors: *Celltec-UB, Department of Cell Biology, and Department of Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; and University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom.
authors: Cathy
authors: C
authors: Tournier
authors: *Celltec-UB, Department of Cell Biology, and Department of Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; and University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom eespel@ub.edu mreina@ub.edu.
authors: Manuel
authors: M
authors: Reina
authors: *Celltec-UB, Department of Cell Biology, and Department of Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; and University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom eespel@ub.edu mreina@ub.edu.
authors: Enric
authors: E
authors: Espel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D048054:Mitogen-Activated Protein Kinase 7
keywords: MAPK; TCR down-regulation; regulatory T cell; ubiquitination