IDENTIFICATION OF AN INHIBIN RECEPTOR IN GONADAL TUMORS FROM INHIBIN ALPHA-SUBUNIT KNOCKOUT MICE

Inhibins and activins are dimeric proteins that are functional antagon ists and are structurally related to the transforming growth factor-be ta (TGF beta) family of growth and differentiation factors. Receptors for activin and TGF beta have been identified as dimers of serine thre onine kinase subunits that regulate cytoplasmic proteins known as Smad s, Despite major advances in our understanding of activin and TGF beta receptors and signaling pathways, little is known about inhibin recep tors or the mechanism by which this molecule provides a functionally a ntagonistic signal to activin. Studies described in this paper indicat e that an independent inhibin receptor exists, Numerous tissues were e xamined for inhibin-specific binding sites, including the developing e mbryo, in which the spinal ganglion and trigeminal ganglion-bound iodi nated inhibin A. Sex cord stromal tumors, derived from male and female inhibin Lu-subunit deficient mice, were also identified as a source o f inhibin receptor, Abundant inhibin and few activin binding sites wer e identified in tumor tissue sections by in situ ligand binding using iodinated recombinant human inhibin A and I-125-labeled recombinant hu man inhibin A, Tumor cell binding was specific for each ligand (compet ed by excess unlabeled homologous ligand and not competed by heterolog ous ligand). Based on these results and the relative abundance and hom ogeneity of tumor tissues versus the embryonic ganglion, tumor tissues were homogenized, membrane proteins were purified, and putative inhib in receptors were isolated using an inhibin affinity column, Four prot eins were eluted from the column that bind iodinated inhibin but not i odinated activin. These data suggest that inhibin-specific membrane-as sociated proteins (receptors) exist.