Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production

Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):134-8. doi: 10.1073/pnas.0608388103. Epub 2006 Nov 9.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • Caspases / physiology*
  • Cells, Cultured
  • Interleukin-6 / biosynthesis*
  • Lysophospholipids / pharmacology*
  • Mice
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / physiology*
  • Protein Kinase C / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • Interleukin-6
  • Lysophospholipids
  • NF-kappa B
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • lysophosphatidic acid