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PNAS 104 (1): 134-138

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY / MEDICAL SCIENCES

Bcl10 and Malt1 control lysophosphatidic acid-induced NF-{kappa}B activation and cytokine production

Stefanie Klemm*, Stephanie Zimmermann*, Christian Peschel*, Tak W. Mak{dagger},{ddagger}, and Jürgen Ruland*,{ddagger}

*Third Medical Department, Technical University of Munich, Klinikum Rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany; and {dagger}The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, ON, Canada M5G 2C1

Contributed by Tak W. Mak, September 25, 2006

Abstract: Lysophosphatidic acid (LPA) is a potent bioactive phospholipid that stimulates a variety of cellular responses by acting on cognate G protein-coupled receptors (GPCRs). There is increasing evidence that LPA signaling reprograms gene expression, but the GPCR-induced pathways connecting LPA receptor stimulation to downstream transcription factors are not well characterized. Here, we identify the adapter proteins Bcl10 and Malt1 as essential mediators of LPA-induced NF-{kappa}B activation. Both proteins were previously known to activate NF-{kappa}B in response to antigen receptor ligation on lymphocytes, but their functions in nonimmune cells are still largely undefined. By using murine embryonic fibroblasts from Bcl10- or Malt1-deficient mice as a genetic model, we report that Bcl10 and Malt1 are critically required for the degradation of I{kappa}B-{alpha} and the subsequent NF-{kappa}B induction in response to LPA stimulation. Bcl10 and Malt1 cooperate with PKCs selectively for LPA-induced NF-{kappa}B activation but are dispensable for the activation of the Jnk, p38, Erk MAP kinase, and Akt signaling pathways. In a biological readout, we demonstrate that LPA-induced IL-6 production is abolished in the absence of Bcl10. Thus, our results identify a NF-{kappa}B-inducing signaling pathway downstream of GPCRs and reveal previously unrecognized functions for Bcl10/Malt1 signaling in nonimmune cells.

Key Words: G protein-coupled receptor • signal transduction

Author contributions: J.R. and T.W.M. designed research; S.K. and S.Z. performed research; S.K., S.Z., C.P., T.W.M., and J.R. analyzed data; and S.K., T.W.M., and J.R. wrote the paper.

The authors declare no conflict of interest.

{ddagger}To whom correspondence may be addressed. E-mail: tmak{at}uhnres.utoronto.ca or jruland{at}lrz.tum.de

© 2007 by The National Academy of Sciences of the USA

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