Background:

The Activin type I receptors transduce signals for a variety of members of the Transforming growth factor beta superfamily of ligands. This family of cytokines and hormones include activin, Anti-müllerian hormone (AMH), bone morphogenetic proteins (BMPs), and Nodal. They are involved in a host of physiological processes including, growth, cell differentiation, homeostasis, osteogenesis, apoptosis and many other functions. There are three type I Activin receptors: ACVR1, ACVR1B, and ACVR1C. Each bind to a specific type II receptor-ligand complex. Despite the large amount of processes that these ligands regulate, they all operate through essentially the same pathway: A ligand binds to a Type two receptor, which recruits and trans-phosphorylate a type I receptor. The type I receptor recruits a receptor regulated SMAD (R-SMAD) which it phosphorylates. The RSMAD then translocates to the nucleus where it functions as a transcription factor.

Activin isoforms and other members of the TGF-β superfamily exert their biological effects by binding to heteromeric complexes of a type I and a type II serine-threonine kinase receptor, both of which are essential for signal transduction. To date, seven type I and five type II receptors, including the two type I and the two type II activin receptors, designated ActR-I(A), ActR-IB, ActR-II(A) and ActR-IIB, have been cloned from mammals. Through alternative mRNA splicing, multiple ActR-IIB isoforms can also be generated, adding to the complexity of the activin receptor system. Different activin isoforms bind with different high-affinities to the various type II isoforms. Type I activin receptors do not bind directly to activin but will associate with the type II receptor-activin complex and initiate signal transduction. Besides the activin isoforms, ActR-II will also bind inhibin, BMP-2 and BMP-7 with lower affinities. ActR-I can also bind and form signaling complexes with the BMP-2/7-bound BMPR-II. Activin type I receptors are highly conserved. Human, mouse and bovine type IA activin receptors share greater than 98% amino acid sequence homology. Recombinant soluble activin type I receptor does not bind activin.