TGF-β and the Smad signal transduction pathway

Transforming growth factor beta (TGF-beta) superfamily members are important regulators of many diverse developmental and homeostatic processes and disruption of their activity has been implicated in a variety of human diseases ranging from cancer to chondrodysplasias and pulmonary hypertension. TGF-beta family members signal through transmembrane Ser-Thr kinase receptors that directly regulate the intracellular Smad pathway. Smads are a unique family of signal transduction molecules that can transmit signals directly from the cell surface receptors to the nucleus, where they regulate transcription by interacting with DNA binding partners as well as transcriptional coactivators and corepressors. In addition, more recent evidence indicates that Smads can also function both as substrates and adaptors for ubiquitin protein ligases, which mediate the targeted destruction of intracellular proteins. Smads have thus emerged as multifunctional transmitters of TGF-beta family signals that play critical roles in the development and homeostasis of metazoans.