Abstract
The nonclassical androgen signaling pathway translates signals into alterations in cellular function within minutes, and this action is proposed to be mediated by an androgen receptor (AR) localized to the plasma membrane. This study was designed to determine the mechanism underlying the membrane association of androgen receptor in TM4 cells, a mouse Sertoli cell line. Western blot analysis indicated testosterone-induced AR translocation to the cell membrane. Data from coimmunoprecipitation indicated that AR is associated with caveolin-1, and testosterone enhanced this association. Knockdown of caveolin-1 by shRNA decreased the amount of AR localized to membrane fraction and prevented AR membrane trafficking after being exposed to testosterone at physiological concentration. The palmitoylation inhibitor 2-bromopalmitate decreased AR membrane localization in basal condition and completely blocked testosterone-induced AR translocation to membrane fraction. These data suggested that AR localized to membrane fraction by binding with caveolin-1 through palmitoylation of the cysteine residue. This study provided a new evidence for AR membrane localization and its application for clarifying the nonclassical signaling pathway of androgens.
Highlights
Male fertility depends on the successful perpetuation of spermatogenesis [1]
It was reported that palmitoylation of a cysteine in the conserved region of estrogen receptor (ER) increases the physical association of ER with caveolin-1 [10], which is the main component of the caveolae in the plasma membranes found in most cell types
We further identified the association of androgen receptor (AR) with caveolin-1 in the membrane fraction
Summary
Cytoplasmic AR translocates to the nucleus and binds to androgen response elements within androgen-responsive genes [3] This process is the classical signaling pathway of testosterone, which requires several hours to respond [3] since it relates to gene transcriptional activation or repression, as well as protein synthesis and secretion required to support spermatogenesis [4]. It was reported that palmitoylation of a cysteine in the conserved region of estrogen receptor (ER) increases the physical association of ER with caveolin-1 [10], which is the main component of the caveolae in the plasma membranes found in most cell types This proteinprotein interaction was required for membrane localization. These data suggested that testosterone induced AR membrane association with caveolin-1 by palmitoylation
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