The TGFbeta Superfamily Signaling Pathway

The transforming growth factor (TGF) beta superfamily of secreted factors is comprised of over 30 members including Activins, Nodals, Bone Morphogenetic Proteins (BMPs), and Growth and Differentiation Factors (GDFs). Members of the family, which are found in both vertebrates and invertebrates, are ubiquitously expressed in diverse tissues and function during the earliest stages of development and throughout the lifetime of animals. Indeed, key roles in embryonic stem cell self-renewal, gastrulation, differentiation, organ morphogenesis, and adult tissue homeostasis have been delineated. Consistent with this ubiquitous activity, aberrant TGFbeta superfamily signaling is associated with a wide range of human pathologies including autoimmune, cardiovascular and fibrotic diseases, as well as cancer. TGFbeta superfamily ligands signal through cell-surface serine/threonine kinase receptors to the intracellular Smad proteins, which in turn accumulate in the nucleus to regulate gene expression. In addition to this universal cascade, Smadin-dependent pathways are also employed in a cell-specific manner to transduce TGFbeta signals. Ligand access to the signaling receptors is regulated by numerous secreted agonists and antagonists and by membrane-associated coreceptors that act in a context-dependent manner. Given the fundamental role of the TGFbeta superfamily in metazoans and the diversity of biological responses, it is not surprising that the signaling pathway is subject to tight and complex regulation at levels both outside and inside the cell. (C) 2012 Wiley Periodicals, Inc.