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J. Biol. Chem., Vol. 281, Issue 45, 34705-34715, November 10, 2006

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Spatial Compartmentalization of Tumor Necrosis Factor (TNF) Receptor 1-dependent Signaling Pathways in Human Airway Smooth Muscle Cells

LIPID RAFTS ARE ESSENTIAL FOR TNF--MEDIATED ACTIVATION OF RhoA BUT DISPENSABLE FOR THE ACTIVATION OF THE NF-B AND MAPK PATHWAYS^*

From the School of Medical Sciences, University of Aberdeen, IMS Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom

Tumor necrosis factor (TNF)--induced activation of RhoA, mediated by TNF receptor 1 (TNFR1), is a prerequisite step in a pathway that leads to increased 20-kDa light chain of myosin (MLC₂₀) phosphorylation and airway smooth muscle contraction. In this study, we have investigated the proximal events in TNF--induced RhoA activation. TNFR1 is localized to both lipid raft and nonraft regions of the plasma membrane in primary human airway smooth muscle cells. TNF- engagement of TNFR1 recruited the adaptor proteins TRADD, TRAF-2, and RIP into lipid rafts and activated RhoA, NF-B, and MAPK pathways. Depletion of cholesterol from rafts with methyl--cyclodextrin caused a redistribution of TNFR1 to nonraft plasma membrane and prevented ligand-induced RhoA activation. By contrast, TNF--induced activation of NF-B and MAPKs was unaffected by methyl--cyclodextrin indicating that, in airway smooth muscle cells, activation of these pathways occurred independently of lipid rafts. Targeted knockdown of caveolin-1 completely abrogated TNF--induced RhoA activation, identifying this raft-resident protein as a positive regulator of the activation process. The signaling adaptors TRADD and RIP were also found to be necessary for ligand-induced RhoA activation. Taken together, our results suggest that in airway smooth muscle cells, spatial compartmentalization of TNFR1 provides a mechanism for generating distinct signaling outcomes in response to ligand engagement and define a mechanistic role for lipid rafts and caveolin-1 in TNF--induced activation of RhoA.

Received for publication, June 15, 2006 , and in revised form, August 21, 2006.

^* This study was supported by The Wellcome Trust, UK. 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. Tel.: 44-1224-555895; Fax: 44-1224-555844; E-mail: i.hunter{at}abdn.ac.uk.

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