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J. Biol. Chem., Vol. 283, Issue 37, 25364-25371, September 12, 2008

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cAMP-dependent Protein Kinase A (PKA) Signaling Induces TNFR1 Exosome-like Vesicle Release via Anchoring of PKA Regulatory Subunit RIIβ to BIG2^*

Aminul Islam, Heather Jones, Toyoko Hiroi, Jonathan Lam, Jing Zhang, Joel Moss, Martha Vaughan, and Stewart J. Levine¹

From the Pulmonary and Vascular Medicine Branch and Translational Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1590

The 55-kDa TNFR1 (type I tumor necrosis factor receptor) can be released to the extracellular space by two mechanisms, the proteolytic cleavage and shedding of soluble receptor ectodomains and the release of full-length receptors within exosome-like vesicles. We have shown that the brefeldin A-inhibited guanine nucleotide exchange protein BIG2 associates with TNFR1 and selectively modulates the release of TNFR1 exosome-like vesicles via an ARF1- and ARF3-dependent mechanism. Here, we assessed the role of BIG2 A kinase-anchoring protein (AKAP) domains in the regulation of TNFR1 exosome-like vesicle release from human vascular endothelial cells. We show that 8-bromo-cyclic AMP induced the release of full-length, 55-kDa TNFR1 within exosome-like vesicles via a protein kinase A (PKA)-dependent mechanism. Using RNA interference to decrease specifically the levels of individual PKA regulatory subunits, we demonstrate that RIIβ modulates both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles. Consistent with its AKAP function, BIG2 was required for the cAMP-induced PKA-dependent release of TNFR1 exosome-like vesicles via a mechanism that involved the binding of RIIβ to BIG2 AKAP domains B and C. We conclude that both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles occur via PKA-dependent pathways that are regulated by the anchoring of RIIβ to BIG2 via AKAP domains B and C. Thus, BIG2 regulates TNFR1 exosome-like vesicle release by two distinct mechanisms, as a guanine nucleotide exchange protein that activates class I ADP-ribosylation factors and as an AKAP for RIIβ that localizes PKA signaling within cellular TNFR1 trafficking pathways.

Received for publication, June 30, 2008

^* This work was supported, in whole or in part, by the Division of Intramural Research, NHLBI, National Institutes of Health. 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.

¹ To whom correspondence should be addressed: Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bldg. 10, Rm. 6D03, MSC 1590, Bethesda, MD 20892-1590. Tel.: 301-402-1448; Fax: 301-496-2363; E-mail: levines{at}nhlbi.nih.gov.

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