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J. Biol. Chem., Vol. 282, Issue 48, 35308-35317, November 30, 2007

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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. Xavier¹, and Daniel K. Podolsky¹²

From the Gastroenterology Unit, Center for the Study of Inflammatory Bowel Disease, and Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Members of the guanine exchange factor (GEF) family of scaffold 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-B 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-B activation and reduced secretion of interleukin-8 and MCP-1 in response to specific ligand stimulation. Furthermore, NF-B 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-B activation and suggest that GEF-containing scaffold proteins may confer specificity to innate immune responses downstream of TLRs.

Received for publication, May 30, 2007 , and in revised form, September 12, 2007.

^* This work was supported by National Institutes of Health Grants DK060049 and DK043351. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Gastroenterology Unit, Jackson Bldg., Rm. 719, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Tel.: 617-726-7411; Fax: 617-726-3673; E-mail: dpodolsky{at}partners.org.

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