An alternative mode ofCD43 signal transduction activates pro‐survival pathways of T lymphocytes

Abstract

SummaryCD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling 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 signalling 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 of Y 705 of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-jB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling 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.

Chitosan from Crabs (Scylla serrata) Represses Hyperlipidemia-Induced Hepato-Renal Dysfunctions in Rats: Modulation of CD43 and p53 Expression

“…Recently, the inherent pro-inflammatory role of CD43; a co-stimulatory molecule of the T-cells were identified. It was shown that CD43 possesses the intrinsic ability to activate the NF-κB and cAMP response element-binding protein (CREB) pathways [ 30 ]. Furthermore, CD43 has been suggested to coordinate the expression of multiple cytokine genes and act as a chemotactic factor with a pro-adhesive role [ 30 , 31 ].…”

“…It was shown that CD43 possesses the intrinsic ability to activate the NF-κB and cAMP response element-binding protein (CREB) pathways [ 30 ]. Furthermore, CD43 has been suggested to coordinate the expression of multiple cytokine genes and act as a chemotactic factor with a pro-adhesive role [ 30 , 31 ]. This study for the first time investigated the possible modulatory effects of chitosan on the expression of hepatic and renal p53 and CD43, as well as hepato-renal functionality of hyperlipidemic rats.…”

Protein kinase function of pyruvate kinase M2 and cancer

“…PKM2 can also directly phosphorylate transcription factor and regulate its transactivation activity [ 20 ]. Nuclear PKM2 has been demonstrated to phosphorylate STAT3 at Tyr705 using a phosphate group from PEP, subsequently activating transcription of MEK5 [ 20 , 73 ] and HIF-1α [ 15 ]. The interaction of polypyrimidine tract-binding protein (PTBP1) and PKM2 facilitates phosphorylation of STAT3 Tyr705 and promotes oncogenesis in lymphoma [ 74 ].…”

Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment

“…Apart from these signaling molecules, some co-stimulatory molecules found on T-cell surface like CD43 also affect PKM2 expression and proliferation, activation and migration of T cells [86]. CD43 and TCR cosignaling stimulates the phosphorylation of Y105 of PKM2 and Y705 of Signal transducer and activator of transcription 3 (STAT3) transducer molecules resulting in the activation of MEPK5/ERk5 pathway which activates nuclear localization kappa B (NF-kB), Myc as well as Bcl-2-associated death promoter (BAD) phosphorylation promoting the survival [87]. Abnormal expression of this protein is also observed in some non-hematologic neoplasms such as lung, colon, and salivary gland cancers [86].…”