Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor.
Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor beta (TGFbeta) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17-20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with (125)I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFbeta family.
Renlund
Nina
N
Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Thier 913, 55 Fruit Street, Boston, Massachusetts 02114, USA.
O'Neill
Francis H
FH
Zhang
LiHua
L
Sidis
Yisrael
Y
Teixeira
Jose
J
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002461:Cell Line, Transformed; D047468:Immunoprecipitation; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D014162:Transfection / Q000379:methods
D034741:RNA, Small Interfering; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C084621:anti-Mullerian hormone receptor; D028341:Activins; D054304:Anti-Mullerian Hormone; D013254:Steroid 17-alpha-Hydroxylase; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498943:Acvr1 protein, mouse; C425585:activin receptor type II-A