Receptors for androgen-binding proteins: Internalization and intracellular signalling

Evidence that androgen-binding proteins bind to membrane receptors, and, in some cells, this binding stimulates cAMP accumulation, and transfer TeBG/ABP into tissue as a consequence of receptor mediated endocytosis, supports the hypothesis that extracellular SHBG is a regulator of cellular function through a membrane receptor that is coupled to adenylate cyclase.

Abstract

In plasma, most steroid hormones are bound and transported by the specific binding protein, testosterone-estradiol-binding globulin (TeBG). For years, it was believed that the only function of this protein was to regulate the concentration of free steroids in plasma. However, a number of reports have provided evidence for the presence of specific TeBG receptors on plasma membranes. Furthermore, the interaction of TeBG with its receptor was shown to be inhibited when steroids are bound to TeBG, suggesting that TeBG is an allosteric protein. The purpose of this manuscript is to review the evidence that androgen-binding proteins bind to membrane receptors, and, in some cells, this binding stimulates cAMP accumulation, and transfer TeBG/ABP into tissue as a consequence of receptor mediated endocytosis. Recent studies from our laboratories have demonstrated binding and uptake of TeBG by MCF-7 breast cancer cells. The interaction of unligated rabbit TeBG with membranes from MCF-7 cells resulted in a time and concentration-dependent increase in adenylate cyclase activity. The TeBG alone also had a reproducible effect on intact cells by increasing cAMP accumulation by 30-35%. The addition of DHT to cells, after TeBG has been allowed to bind, resulted in increases in cAMP of greater than 4-fold. This effect was not blocked by antiandrogens. These data support the hypothesis that extracellular SHBG is a regulator of cellular function through a membrane receptor that is coupled to adenylate cyclase.