HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 40, 29584-29593, October 5, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/40/29584    most recent M703310200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cinar, B. Articles by Freeman, M. R. Search for Related Content PubMed PubMed Citation Articles by Cinar, B. Articles by Freeman, M. R. Social Bookmarking                      What's this?

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains^*

Bekir Cinar¹, Nishit K. Mukhopadhyay, Gaoyuan Meng, and Michael R. Freeman²

From the Urological Diseases Research Center, Departments of Urology, Surgery and Biological Chemistry and Molecular Pharmacology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115

The serine-threonine kinase, Akt1/protein kinase B is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting non-genomic signals involving androgen and the Akt pathway in prostate cancer cells.

Received for publication, April 19, 2007 , and in revised form, July 2, 2007.

^* The work was supported in part by National Institutes of Health Grants R37 DK47556, R01 CA112303, and P50 DK65298 (to M. R. F.), and a pilot grant from the Harvard Prostate Cancer SPORE (to M. R. F.). 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 Figs. S1-S3.

¹ American Urological Association Foundation Research Scholar and supported in part by a fellowship from the United States Department of Defense Grant W81XWH-04-1-0296.

² To whom correspondence should be addressed: John F. Enders Research Laboratories, Suite 1161, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2644; Fax: 617-730-0238; E-mail: michael.freeman{at}childrens.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Miersch, M. G. Espey, R. Chaube, A. Akarca, R. Tweten, S. Ananvoranich, and B. Mutus Plasma Membrane Cholesterol Content Affects Nitric Oxide Diffusion Dynamics and Signaling J. Biol. Chem., July 4, 2008; 283(27): 18513 - 18521. [Abstract] [Full Text] [PDF]