Does Megalin Mediate Steroid Hormone Uptake?

Abstract

Androgens and estrogens circulate through the bloodstream bound to sex hormone binding globulin (SHBG), in what has been believed to be an inactive form that prevents these small, lipophilic steroids from diffusing across the plasma membrane to activate intracellular targets (see Adams). A research group that previously showed that the low-density lipoprotein receptor-related protein megalin acts as an endocytic receptor for carrier-bound vitamins A and D has now implicated megalin in the uptake of SHBG-bound sex steroids. Hammes et al. showed that 125 I-labeled SHBG was taken up and degraded by rat choriocarcinoma (BN16) cells, which express megalin, and that this was blocked by receptor-associated protein (RAP), an antagonist of ligand binding to megalin. Most circulating sex steroids are bound to carrier, and the ability of RAP to inhibit [ 3 H]testosterone uptake depended on the ratio of SHBG and testosterone, such that inhibition was maximal when most of the testosterone was bound, whereas RAP was ineffective when most of the testosterone was free. RAP also inhibited the uptake of SHBG-bound dihydrotestosterone (DHT) and 17β-estradiol. Uptake of fluorescein isothiocyanate (FITC)-labeled DHT together with SHBG was confirmed with confocal immunofluorescence microscopy; moreover, DHT internalized together with SHBG activated an androgen-sensitive reporter. The phenotypes of megalin knockout mice were consistent with impaired sex-steroid signaling: Megalin —/— females exhibited vaginal blockade whereas megalin —/— males exhibited impaired descent of the testes. Further, megalin-deficient embryonic tissues were resistant to the effects of exogenous androgens. Thus, the authors conclude that megalin plays a role in the cellular uptake of carrier-bound sex steroids that is critical to the proper development of steroid-responsive tissues. A. Hammes, T. K. Andreassen, R. Spoelgen, J. Raila, N. Hubner, H. Schulz, J. Metzger, F. J. Schweigert, P. B. Luppa, A. Nykjaer, T. E. Willnow, Role of endocytosis in cellular uptake of sex steroids. Cell 122 , 751-762 (2005). [PubMed] J. S. Adams, "Bound" to work: The free hormone hypothesis revisited. Cell 122 , 647-649 (2005). [PubMed]