Identification of an inhibin receptor in gonadal tumors from inhibin alpha-subunit knockout mice.
Inhibins and activins are dimeric proteins that are functional antagonists and are structurally related to the transforming growth factor-beta (TGFbeta) family of growth and differentiation factors. Receptors for activin and TGFbeta have been identified as dimers of serine-threonine kinase subunits that regulate cytoplasmic proteins known as Smads. Despite major advances in our understanding of activin and TGFbeta receptors and signaling pathways, little is known about inhibin receptors or the mechanism by which this molecule provides a functionally antagonistic signal to activin. Studies described in this paper indicate that an independent inhibin receptor exists. Numerous tissues were examined for inhibin-specific binding sites, including the developing embryo, in which the spinal ganglion and trigeminal ganglion-bound iodinated inhibin A. Sex cord stromal tumors, derived from male and female inhibin alpha-subunit-deficient mice, were also identified as a source of inhibin receptor. Abundant inhibin and few activin binding sites were identified in tumor tissue sections by in situ ligand binding using iodinated recombinant human inhibin A and 125I-labeled recombinant human inhibin A. Tumor cell binding was specific for each ligand (competed by excess unlabeled homologous ligand and not competed by heterologous ligand). Based on these results and the relative abundance and homogeneity of tumor tissues versus the embryonic ganglion, tumor tissues were homogenized, membrane proteins were purified, and putative inhibin receptors were isolated using an inhibin affinity column. Four proteins were eluted from the column that bind iodinated inhibin but not iodinated activin. These data suggest that inhibin-specific membrane-associated proteins (receptors) exist.
Draper
L B
LB
Department of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Matzuk
M M
MM
Roberts
V J
VJ
Cox
E
E
Weiss
J
J
Mather
J P
JP
Woodruff
T K
TK
D029404:Activin Receptors; D028341:Activins; D000818:Animals; D001345:Autoradiography; D005260:Female; D007265:Inhibins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism*; D011869:Radioligand Assay; D018000:Receptors, Peptide / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018312:Sex Cord-Gonadal Stromal Tumors / Q000378:metabolism*
D008565:Membrane Proteins; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D028341:Activins; D007265:Inhibins; D029404:Activin Receptors