AKAP13, a RhoA GTPase-specific guanine exchange factor, is a novel regulator of TLR2 signaling

Oren Shibolet, Cosmas Giallourakis, Ian Rosenberg, Tobias Mueller, Ramnik J. Xavier, Daniel K. Podolsky

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Members of the guanine exchange factor (GEF) family of scaf-fold proteins are involved in the integration of signal flow downstream of many receptors in adaptive immunity. However, the full complement of GEFs that function downstream of Toll-like receptors (TLRs) requires further identification and functional understanding. By systematically integrating expression profiles from immune and epithelial cells with functional studies, we demonstrate that protein kinase A anchoring protein 13 (AKAP13), a scaffold protein with GEF activity, is an activator of NF-κB downstream of TLR2 signaling. Stimulation of the human macrophage cell line THP-1 and epithelial cells with a TLR2 ligand caused a significant up-regulation in AKAP13 mRNA, corresponding to an increase in protein expression. Analysis of TLR2 reporter cell lines deficient in AKAP13 expression revealed significantly reduced NF-κB activation and reduced secretion of interleukin-8 and MCP-1 in response to specific ligand stimulation. Furthermore, NF-κB activation was partially inhibited by a GEF-deficient AKAP13 mutant. AKAP13 was also involved in phosphorylation of JNK but not of extracellular signal-regulated kinase ERK1 and -2 following ligand stimulation. Together, our results suggest that AKAP13 plays a role in TLR2-mediated NF-κB activation and suggest that GEF-containing scaffold proteins may confer specificity to innate immune responses downstream of TLRs.

Original languageEnglish (US)
Pages (from-to)35308-35317
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number48
DOIs
StatePublished - Nov 30 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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