Bcl10 and Malt1 control lysophosphatidic acid- induced NF-{kappa}B activation and cytokine production.
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-kappaB activation. Both proteins were previously known to activate NF-kappaB 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 IkappaB-alpha and the subsequent NF-kappaB induction in response to LPA stimulation. Bcl10 and Malt1 cooperate with PKCs selectively for LPA- induced NF-kappaB 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-kappaB- inducing signaling pathway downstream of GPCRs and reveal previously unrecognized functions for Bcl10/ Malt1 signaling in nonimmune cells.[1]References
- Bcl10 and Malt1 control lysophosphatidic acid-induced NF-{kappa}B activation and cytokine production. Klemm, S., Zimmermann, S., Peschel, C., Mak, T.W., Ruland, J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
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