TYPE-I RECEPTORS SPECIFY GROWTH-INHIBITORY AND TRANSCRIPTIONAL RESPONSES TO TRANSFORMING GROWTH-FACTOR-BETA AND ACTIVIN

Transforming growth factor beta (TGF-beta) and activin bind to recepto r complexes that contain two distantly related transmembrane serine/th reonine kinases known as receptor types I and II. The type II receptor s determine ligand binding specificity, and each interacts with a dist inct repertoire of type I receptors. Here we identify a new type I rec eptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. Act R-IB has the structural and binding properties of a type I receptor: i t binds activin only in the presence of an activin type II receptor an d forms a heteromeric noncovalent complex with activin type II recepto rs. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a co mmon set of growth-inhibitory and transcriptional responses in associa tion with their corresponding ligands and type II receptors. The trans criptional responses include elevated expression of fibronectin and pl asminogen activator inhibitor 1. Although T beta R-I and ActR-IB are n early identical in their kinase domains (90% amino acid sequence ident ity), their corresponding type II receptor kinase domains are very dif ferent from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin corre lates with the presence of similar type I kinases in their complex. In deed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) w hose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, eve conclude t hat the type I receptor subunits are primary specifiers of signals sen t by TGF-beta and activin receptor complexes.