The orphan ligand, activin C, signals through activin receptor-like kinase 7.

Autor:	Goebel EJ; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States., Ongaro L; Department of Pharmacology and Therapeutics, Centre for Research in Reproduction and Development, McGill University, Montreal, Canada., Kappes EC; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States., Vestal K; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States., Belcheva E; Merck &Co., Inc., Kenilworth, United States., Castonguay R; Merck &Co., Inc., Kenilworth, United States., Kumar R; Merck &Co., Inc., Kenilworth, United States., Bernard DJ; Department of Pharmacology and Therapeutics, Centre for Research in Reproduction and Development, McGill University, Montreal, Canada., Thompson TB; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Jun 23; Vol. 11. Date of Electronic Publication: 2022 Jun 23.
DOI:	10.7554/eLife.78197
Abstrakt:	Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; InhβA/InhβA) or activin C (ActC; InhβC/InhβC), or as heterodimers, as with activin AC (ActAC; InhβA:InhβC). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the InhβC chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the InhβC chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins. Competing Interests: EG, LO, EK, KV, DB, TT No competing interests declared, EB, RC, RK Past employee of Acceleron Pharma and is now an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc (© 2022, Goebel et al.)
Databáze:	MEDLINE
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