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J. Biol. Chem., Vol. 282, Issue 31, 22278-22288, August 3, 2007
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A Conserved Mechanism for Steroid Receptor Translocation to the Plasma Membrane*
¶1
From the
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, California 90822 and the Departments of Medicine, ¶Pharmacology, and Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697
Multiple steroid receptors (SR) have been proposed to localize to the plasma membrane. Some structural elements for membrane translocation of the estrogen receptor 
(ER) have been described, but the mechanisms relevant to other steroid receptors are entirely unknown. Here, we identify a highly conserved 9 amino acid motif in the ligand binding domains (E domains) of human/mouse ER and ER
, progesterone receptors A and B, and the androgen receptor. Mutation of the phenylalanine or tyrosine at position–2, cysteine at position 0, and hydrophobic isoleucine/leucine or leucine/leucine combinations at positions +5/6, relative to cysteine, significantly reduced membrane localization, MAP and PI 3-kinase activation, thymidine incorporation into DNA, and cell viability, stimulated by specific SR ligands. The localization sequence mediated palmitoylation of each SR, which facilitated caveolin-1 association, subsequent membrane localization, and steroid signaling. Palmitoylation within the E domain is therefore a crucial modification for membrane translocation and function of classical sex steroid receptors.
Received for publication, December 28, 2006 , and in revised form, May 2, 2007.
* This work was supported in part by grants from the Research Service of the Department of Veteran's Affairs, and National Institutes of Health Grant CA-100366 (to E. R. L.). 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: Medical Service (111-I)Long Beach VA Medical Center/UC-Irvine, 5901 E. 7th St. Long Beach, CA 90822. Tel.: 562-826-5748; Fax: 562-826-5515; E-mail: ellis.levin{at}med.va.gov.
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