Controlling TGF-β signaling

The transforming growth factor beta (TGF-beta) family of hormonally active polypeptides have attracted much attention because of their ability to control cellular functions that underwrite animal embryo development and tissue homeostasis. TGF-beta family members act by modifying the expression of specific sets of target genes, and biologists pursuing the elucidation of TGF-beta signaling mechanisms have turned up a fairly simple system, linking membrane TGF-beta receptors to such genes (for recent reviews, see Heldin et al. 1997; Massague 1998; Whitman 1998; Massague and Wotton 2000). If a TGF-beta signaling system can be so simple, and yet so powerful, then an elaborate network of regulators must keep control over the inputs, activity, and outcomes of this system. A multitude of regulatory mechanisms have been recently uncovered that control the access of TGF-beta family members to their receptors, the activity of their receptors and receptor substrates, and the nuclear function of the transcriptional complexes generated by this pathway. The regulatory mechanisms operating in the prereceptor phase of a TGF-beta signaling pathway can be as intricate and physiologically important as those operating downstream of TGF-beta receptors. These control mechanisms, which are central to understanding the physiology of TGF-beta signaling, are reviewed here.