EMBO J. 2011 Feb 2;30(3):594-605. Epub 2010 Dec 14.

Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation.External

Eitelhuber, A. C., Warth, S., Schimmack, G., Duwel, M., Hadian, K., Demski, K., Beisker, W., Shinohara, H., Kurosaki, T., Heissmeyer, V., Krappmann, D.,
--- - Department of Cellular Signal Integration, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Institute of Toxicology, Neuherberg, Germany.
The Carma1-Bcl10-Malt1 (CBM) complex bridges T-cell receptor (TCR) signalling to the canonical IkappaB kinase (IKK)/NF-kappaB pathway. NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane. We have identified the serine-threonine protein phosphatase PP2A regulatory subunit Aalpha (PPP2R1A) as a novel interaction partner of Carma1. PPP2R1A is associated with Carma1 in resting as well as activated T cells in the context of the active CBM complex. By siRNA-mediated knockdown and in vitro dephosphorylation, we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. As a result of PP2A inactivation, we find that enhanced Carma1 S645 phosphorylation augments CBM complex formation, NF-kappaB activation and IL-2 or IFN-gamma production after stimulation of Jurkat T cells or murine Th1 cells. Thus, our data define PP2A-mediated dephosphorylation of Carma1 as a critical step to limit T-cell activation and effector cytokine production.
PMID: 21157432External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD Bcl-10 Link CARD11 Co-immunoprecipitation Jurkat 21157432
(Link: click this icon to show interactions only between the two corresponding DDs)