Recombinant Mouse Activin RIIB Fc Chimera Protein, CF

Activin molecules and other members of the TGF-beta superfamily exert their biological effects through heteromeric complexes of type I and a type II serine/threonine kinase receptors (1, 2). Ligands bind to the type II receptor (such as ActRIIB) which then associates with a type I receptor to initiate signal transduction (3, 4). The mature mouse ActRIIB consists of a 119 amino acid (aa) extracellular domain, a 21 aa transmembrane segment, and a 378 aa cytoplasmic region that includes the kinase domain and a C-terminal PDZ-binding motif (5). ActRIIB exists in four alternately spliced forms that are distinguished by the deletion of juxtamembrane stretches in the extra and/or intracellular regions (5). Particular activin isoforms bind with different high affinities to the various type II receptor isoforms (5). Within the ECD, mouse ActRIIB shares 99% aa sequence identity with human and rat ActRIIB. It shares 53% aa sequence identity with ActRIIA. Besides the activin isoforms, ActR-II will also bind inhibin, BMP-2, and BMP-7 with lower affinities. ActRIIB mediated signaling can be modulated by several accessory proteins. Interactions with the GPI linked RGM-A/DRAGON lower the threshold for BMP-2 and BMP-4 induced signaling (6). ActRIIB forms a ternary complex with activin A and cripto which prevents association with the type I receptor ActRIB, thereby interfering with activin induced signaling (7). ActRIIB can also form a ternary complex with activin A and endoglin (8). The C-terminal tail of ActRIIB specifically binds the PDZ domain of the cytoplasmic protein ARIP2 which enhances receptor internalization and hinders activin induced responses (9). Although three variants of ARIP2 have been identified, only the full length isoform modulates ActRII internalization (10).