An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes

CD43 is one of the most abundant co-stimulatory molecules on a T cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulate the outcome of T cell responses. The aim of this study was to uncover new signaling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signaling cascade resulting from the engagement of CD43 and the T cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both, Y(105) of PKM2 and that of Y(705) of signal transducer and activator of transcription 3 (Stat3) was induced in response to TCR+CD43 co-stimulation, resulting in activation of the MEK5/ERK5 pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and NFκB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T cell hybridoma favored cell survival. Altogether, our data highlight novel signaling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes. This article is protected by copyright. All rights reserved.