A CHIMERIC SERINE THREONINE KINASE RECEPTOR SYSTEM REVEALS THE POTENTIAL OF MULTIPLE TYPE-II RECEPTORS TO COOPERATE WITH TRANSFORMING GROWTH-FACTOR-BETA TYPE-I RECEPTOR/

Receptor-type serine/threonine kinases (RSKs) have been organized into two distinct classes known as types I and II on the basis of sequence similarity. However, experiments have shown ligand specificities in t he two classes and as a result type I and type II receptors can often bind to a common ligand. The transforming growth factor-beta- (TGF-bet a) specific receptors represent such a case, where both type I and II receptors (T beta RI and T beta RII) are observed. Of additional inter est is the observation that heteromeric associations of type I and II receptors can also enable signaling. To further elucidate the function of various RSKs, the extracellular domains of both alpha and beta cha ins from human granulocyte-macrophage colony-stimulating factor recept ors were linked to transmembrane cytoplasmic domains of RSKs. Chimeric receptors of human granulocyte-macrophage receptor (hGMR) alpha with T beta RI and hGMR beta with T beta RII were expressed in murine pre-B cell-derived Ba/F3 cells. These chimeras formed heteromeric complexes , transmitted TGF-beta signals, and were down-modulated in response to human granulocyte-macrophage colony-stimulating factor. However, expe riments utilizing these chimeric receptors in different combinations r evealed that only heteromeric associations of transmembrane cytoplasmi c domains mediated signaling and down-modulation. Chimeric receptors w ith transmembrane cytoplasmic domains of activin receptor type II and bone morphogenetic protein receptor type II also provided signals in c onjunction with chimeric T beta RI. As a result, these type II recepto rs may share a common potential to signal via T beta RI. hGMR-RSK chim eric receptors may be useful tools for the identification and characte rization of the divergent signals mediated by individual RSKs.