Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation.
Transforming growth factor-beta (TGF-beta) represents an evolutionarily conserved family of secreted factors that mobilize a complex signaling network to control cell fate by regulating proliferation, differentiation, motility, adhesion, and apoptosis. TGF-beta promotes the assembly of a cell surface receptor complex composed of type I (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 regulatory GS-domain. Activated T beta RI then initiates cytoplasmic signaling pathways to produce cellular responses. SMAD proteins together constitute a unique signaling pathway with key roles in signal transduction by TGF-beta and related factors. Pathway-restricted SMADs are phosphorylated and activated by type I receptors in response to stimulation by ligand. Once activated, pathway-restricted SMADs oligomerize with the common-mediator Smad4 and subsequently translocate to the nucleus. Genetic analysis in Drosophila melanogaster and Caenorhabditis elegans, as well as T beta RII and SMAD mutations in human tumors, emphasizes their importance in TGF-beta signaling. Mount ng evidence indicates that SMADs cooperate with ubiquitous cytoplasmic signaling cascades and nuclear factors to produce the full spectrum of TGF-beta responses. Operating independently, these ubiquitous elements may influence the nature of cellular responses to TGF-beta. Additionally, a variety of regulatory schemes contribute temporal and/or spatial restriction to TGF-beta responses. This report reviews our current understanding of TGF-beta signal transduction and considers the importance of a cooperative signaling paradigm to TGF-beta-mediated biological responses.
Engel
M E
ME
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-6838, USA.
Datta
P K
PK
Moses
H L
HL
D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta