Dual role of ERK5 in the regulation of T cell receptor expression at the T cell surface.

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.