Signal transduction by transforming growth factor-beta: A cooperative paradigm with extensive negative regulation

Transforming growth factor-beta (TGF-beta) represents an evolutionarily con served family of secreted factors that mobilize a complex signaling network to control cell fate by regulating proliferation, differentiation, motilit y, adhesion, and apoptosis. TGF-beta promotes the assembly of a cell surfac e receptor complex composed of type 1 (T beta RI) and type II (T beta RII) receptor serine/threonine kinases. In response to TGF-beta binding, T beta RII recruits and activates T beta RI through phosphorylation of the regulat ory GS-domain. Activated T beta RI then initiates cytoplasmic signaling pat hways to produce cellular responses. SMAD proteins together constitute a un ique signaling pathway with key roles in signal transduction by TGF-beta an d related factors. Pathway-restricted SMADs are phosphorylated and activate d by type I receptors in response to stimulation by ligand. Once activated, pathway-restricted SMADs oligomerize with the common-mediator Smad4 and su bsequently translocate to the nucleus. Genetic analysis in Drosophila melan ogaster and Caenorhabditis elegans, as well as T beta RII and SMAD mutation s in human tumors, emphasizes their importance in TGF-beta signaling. Mount ing evidence indicates that SMADs cooperate with ubiquitous cytoplasmic sig naling cascades and nuclear factors to produce the full spectrum of TGF-bet a responses. Operating independently, these ubiquitous elements may influen ce the nature of cellular responses to TGF-beta. Additionally, a variety of regulatory schemes contribute temporal and/or spatial restriction to TGF-b eta responses. This report reviews our current understanding of TGF-beta si gnal transduction and considers the importance of a cooperative signaling p aradigm to TGF-beta-mediated biological responses. J. Cell. Biochem. Suppls . 30/31.:111-122, 1998. (C) 1998 Wiley-Liss, Inc.