title: A conserved mechanism for steroid receptor translocation to the plasma membrane.
abstract: Multiple steroid receptors (SR) have been proposed to localize to the plasma membrane. Some structural elements for membrane translocation of the estrogen receptor alpha (ER alpha) 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 alpha and ER beta, 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.
authors.affiliation: Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, California 90822, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Pedram
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Razandi
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Sainson
authors.forename: Jin K
authors.initials: JK
authors.lastname: Kim
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Hughes
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051242:Caveolin 1; D011987:Receptors, Steroid; D019869:Phosphatidylinositol 3-Kinases