HUMAN TYPE-II RECEPTOR FOR BONE MORPHOGENIC PROTEINS (BMPS) - EXTENSION OF THE 2-KINASE RECEPTOR MODEL TO THE BMPS

Bone morphogenic proteins (BMPs) are universal regulators of animal de velopment. We report the identification and cloning of the BMP type II receptor (BMPR-II), a missing component of this receptor system in ve rtebrates. BMPR-II is a transmembrane serine/threonine kinase that bin ds BMP-2 and BMP-7 in association with multiple type I receptors, incl uding BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. Cloning of BMPR-II resulted from a strong interaction of its cytoplasmic domain with diverse transforming growth factor beta fa mily type I receptor cytoplasmic domains in a yeast two-hybrid system. In mammalian cells, however, the interaction of BMPR-II is restricted to BMP type I receptors and is ligand dependent. BMPR-II binds BMP-2 and -7 on its own, but binding is enhanced by coexpression of type I B MP receptors. BMP-2 and BMP-7 can induce a transcriptional response wh en added to cells coexpressing ActR-I and BMPR-II but not to cells exp ressing either receptor alone. The kinase activity of both receptors i s essential for signaling. Thus, despite their ability to bind to type I and II receptors separately, BMPs appear to require the cooperation of these two receptors for optimal binding and for signal transductio n. The combinatorial nature of these receptors and their capacity to c rosstalk with the activin receptor system may underlie the multifuncti onal nature of their ligands.