Activin Receptor

Activin receptors belong to the TGF-beta receptor superfamily: each is a transmembrane serine/threonine kinase that crosses the membrane once. Two receptor types cooperate. The type II receptor (ActRIIA/ACVR2A or ActRIIB/ACVR2B), which is active at all times, captures the ligand dimer first; it then pulls in a type I receptor (ALK4/ACVR1B, ALK7, or ALK5 for certain ligands) and phosphorylates it. Once switched on, the type I kinase phosphorylates SMAD2 and SMAD3; these partner with SMAD4 and relocate to the nucleus.

Targeting the receptor instead of the ligand

Activin A and B, myostatin, GDF-11 and a number of BMPs all signal through ActRIIB. Because the receptor is so unselective, acting at this level is both attractive and risky: soluble ActRIIB-Fc decoys like ACE-031 soak up the entire ligand family in one go. Large gains in muscle mass were reported in rodents, yet a human trial programme in Duchenne muscular dystrophy was stopped in 2013 after vascular effects such as nosebleeds (epistaxis) and telangiectasia — findings linked to blocking BMP9/10 signalling in addition to myostatin.

Inhibin subunits compete for these receptors as natural antagonists, while follistatin captures the ligands before they can bind at all.

Related terms and material

recombinant · preclinical · in vivo. Reference material: ACE-031, GDF-8 / myostatin propeptide, IGF & muscle peptides.