Transforming growth factor-β blocks inhibin binding to different target cell types in a context-dependent manner through dual mechanisms involving betaglycan

Paul G. Farnworth, Yao Wang, Ruth Escalona, Pauline Leembruggen, Guck T. Ooi, Jock K. Findlay

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27 Citations (Scopus)


Inhibin antagonizes activin and bone morphogenetic protein actions by sequestering their type II receptors in high-affinity complexes with betaglycan, a coreceptor that inhibin shares with TGF-β. To clarify the nature and extent of interactions between inhibin and TGF-β, we therefore examined 1) the mutual competition between these ligands for binding, 2) the regulation of endogenous betaglycan expression by inhibin and TGF-β isoforms, and 3) the consequences of such betaglycan regulation for subsequent inhibin binding in mouse Leydig (TM3), Sertoli (TM4), adrenocortical cancer (AC), and gonadotroph (LβT2) cell lines, chosen to model cellular targets for local and endocrine actions of inhibin. Recognized inhibin, activin, and TGF-β binding proteins and TGF-β/activin signaling components were expressed by all four cell types, but AC and LβT2 cells notably lacked the type II receptor for TGF-β, TβRII. Overnight treatment of TM3 and TM4 cells with TGF-β1 suppressed the levels of betaglycan mRNA by 73 and 46% of control and subsequent [125I]inhibin A binding by 64 and 41% of control (IC50 of 54 and 92 pM), respectively. TGF-β2 acted similarly. TGF-β pretreatments commensurately decreased the [125I]inhibin A affinity labeling of beta-glycan on TM3 and TM4 cells. TGF-β isoforms as direct competitors blocked up to 60% of specific inhibin A binding sites on TM3 and TM4 cells but with 9- to 17-fold lower potency than when acting indirectly via regulation of betaglycan. Only the competitive action of TGF-β was observed with TβRII-deficient AC and LβT2 cells. Neither inhibin A nor inhibin B regulated betaglycan mRNA or competed for binding of [ 125I]TGF-β1 or -β2. Thus, inhibin binding to its target cell types is controlled by TGF-β through dual mechanisms of antagonism, the operation of which vary with cell context and display different sensitivities to TGF-β. In contrast, TGF-β binding is relatively insensitive to the presence of either inhibin A or inhibin B.

Original languageEnglish
Pages (from-to)5355-5368
Number of pages14
Issue number11
Publication statusPublished - Nov 2007

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