ACTIVIN AND INHIBIN HAVE ANTAGONISTIC EFFECTS ON LIGAND-DEPENDENT HETEROMERIZATION OF THE TYPE-I AND TYPE-II ACTIVIN RECEPTORS AND HUMAN ERYTHROID-DIFFERENTIATION

Activins and inhibins belong to the transforming growth factor beta (T GF-beta)-like superfamily and exert their effects on a broad range of cellular targets by modulating cell differentiation and proliferation. Members of this family interact with two structurally related classes of receptors (type I and type II), both containing a serine/threonine kinase domain, When expressed alone, the type II but not the type I a ctivin receptor can bind activin, However, the presence of a type I re ceptor is required for signaling. For TGF-beta 1, ligand binding to th e type II receptor results in the recruitment and transphosphorylation of the type I receptor, Transient overexpression of the two types of activin receptor results in ligand-independent receptor heteromerizati on and activation, Nevertheless, activin addition to the transfected c ells increased complex formation between the two receptors, suggesting a mechanism of action similar to that observed for the TGF-beta recep tor, In the present study, we generated a stable cell line, overexpres sing the two types of activin receptor upon induction, in the human er ythroleukemia cell line K562, We demonstrate here that activin specifi cally induces heteromer formation between the type I and type II recep tors in a time-dependent manner, Using this stable line, we analysed t he effects of activin and inhibin on human erythroid differentiation. Our results indicate that activin signal transduction mediated through its type I and type II receptors results in an increase in the hemogl obin content of the cells and limits their proliferation. Finally, usi ng cell lines that can be induced to overexpress ActRII and ActRIB or ActRIB only, we show that the inhibin antagonistic effects on activin- induced biological responses are mediated through a competition for th e type II activin receptor but also require the presence of an inhibin -specific binding component.