SIGNALING ACTIVITY OF TRANSFORMING GROWTH-FACTOR-BETA TYPE-II RECEPTORS LACKING SPECIFIC DOMAINS IN THE CYTOPLASMIC REGION

The transforming growth factor beta (TGF-beta) type II receptor (Tbeta R-II) is a transmembrane serine/threonine kinase that contains two ins erts in the kinase region and a serine/threonine-rich C-terminal exten sion. TbetaR-II is required for TGF-beta binding to the type I recepto r, with which it forms a heteromeric receptor complex, and its kinase activity is required for signaling by this complex. We investigated th e role of various cytoplasmic regions in TbetaR-II by altering or dele ting these regions and determining the signaling activity of the resul ting products in cell lines made resistant to TGF-beta by inactivation of the endogenous TbetaR-II. TGF-beta binding to receptor I and respo nsiveness to TGF-beta in these cells can be restored by transfection o f wild-type TbetaR-II. Using this system, we show that the kinase inse rt 1 and the C-terminal tail of TbetaR-II, in contrast to the correspo nding regions in most tyrosine kinase receptors, are not essential to specify ligand-induced responses. Insert 2 is necessary to support the catalytic activity of the receptor kinase, and its deletion yields a receptor that is unable to mediate any of the responses tested. Howeve r, substitution of this insert with insert 2 from the activin receptor , ActR-IIB, does not diminish the ability of TbetaR-II to elicit these responses. A truncated TbetaR-II lacking the cytoplasmic domain still binds TGF-beta, supports ligand binding to receptor I, and forms a co mplex with this receptor. However, TGF-beta binding to receptor I faci litated by this truncated TbetaR-II fails to inhibit cell proliferatio n, activate extracellular matrix protein production, or activate trans cription from a promoter containing TGF-beta-responsive elements. We c onclude that the transcriptional and antiproliferative responses to TG F-beta require both components of a heteromeric receptor complex that differs from tyrosine kinase receptors in its mode of signaling.