Role of endocytosis in cellular uptake of sex steroids.
Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.
Hammes
Annette
A
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
Andreassen
Thomas K
TK
Spoelgen
Robert
R
Raila
Jens
J
Hubner
Norbert
N
Schulz
Herbert
H
Metzger
Jochen
J
Schweigert
Florian J
FJ
Luppa
Peter B
PB
Nykjaer
Anders
A
Willnow
Thomas E
TE
D000728:Androgens / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004703:Endocrine System / Q000166:cytology / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D012739:Gonadal Steroid Hormones / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014564:Urogenital Abnormalities / Q000235:genetics / Q000473:pathology; D014566:Urogenital System / Q000196:embryology / Q000473:pathology
D000728:Androgens; D002352:Carrier Proteins; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D012738:Sex Hormone-Binding Globulin; C010140:estrophilin