From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction.

Abstract

Understanding the mechanisms that govern specificity in signal transduction networks is of paramount importance as the ever increasing power of molecular and cellular techniques brings to the surface more and more complex associations between pathways of cell communication. A primary determinant of specificity in all signaling protein networks is the powerful but flexible biochemical “glue” of interacting protein interfaces. When X-ray crystallographers explore this principle at the atomic level, they often reveal beautiful examples of molecular design. One such novel revelation is presented in this issue of Genes & Development by Qin et al. (2002), who describe novel protein interfaces and their dynamic role in controlling specificity during signal transduction by members of the transforming growth factor(TGF) family. TGFand its related growth and morphogenetic protein factors regulate cell proliferation, differentiation, migration, and programmed cell death as well as embryonic development and tissue interactions. Over the past 10 years, the three-dimensional structures of TGFs, themselves, as well as of several components in the signaling pathway, have been solved by X-ray crystallography (for review, see Souchelnytskiy et al. 2002). The pathway initiates with the activation of receptor serine/ threonine kinases (RS/TK) on the cell surface by extracellular ligands, and propagates inside the cell primarily via the Smad family of signal transducers that rapidly translocate to the nucleus (for review, see Moustakas et al. 2001; Attisano and Wrana 2002). Alternative signaling cascades may also be activated by TGFfamily members; however, the Smads represent the major and most direct route of communication between the extracellular milieu and the cell nucleus, the ultimate target of signal transduction pathways (Massague 2000; Wakefield and Roberts 2002). The findings by Qin et al. (2002) suggest a model that integrates molecular events proximal to the cell surface receptors with those occurring in the nucleus during pathway-instructed regulation of gene expression. A major transition that Smad proteins undergo as they move from the receptors to the nucleus is to change from inactive monomers to active trimers. This stoichiometric change regulates molecular specificity in an interesting manner. Pivotal to the understanding of the new model is the modular structure of Smads, which consists of the conserved, globular Mad-homology (MH) domains, MH1 and MH2, in the N and C termini, respectively, bridged by a less conserved and flexible, proline-rich linker (L) domain (Shi 2001).