Transforming growth factor-beta signal transduction.

Abstract

The TGF-β superfamily of cytokines comprises an array of more than two dozen secreted peptides that have been implicated as multifunctional regulators of cell growth, differentiation, and function.1 2 Members of this family are pivotal for normal development in a variety of species, providing diffusible signals that influence pattern formation, body axes, cell fate, and other aspects of morphogenesis. In the embryonic heart, developmental functions for TGF-β inferred from the genes’ program of expression and from model systems for cardiac organogenesis include the specification of cardiogenic precursor cells in lateral mesoderm as well as epithelial-mesenchymal transitions involved in valve formation.2 In postnatal myocardium, TGF-β controls the mixed histocompatibility genes, whose deregulation may explain the myocarditis found in mice lacking TGF-β1. In isolated cardiac muscle cells, TGF-β counters the suppression of myocyte contraction by interleukin-1β, at least in part through a block to induction of nitric oxide synthase. Conversely, TGF-β evokes a “fetal” program of myocardial gene expression, which, together with the upregulation of TGF-β by mechanical load and other trophic signals, suggests the operation of an autocrine or paracrine loop in certain forms of cardiac hypertrophy.2 The TGF-β superfamily consists of at least 25 different peptides, classified into three subgroups based on sequence similarities: (1) TGF-βs themselves, of which three isoforms are found in mammals, (2) activins, and (3) a complex third subfamily of proteins (BMPs, nodal, Xenopus Vg-1, Drosophila dpp, and screw) with prominent effects on mesoderm induction and formation of axial structures.1 2 All known members of the superfamily are produced as large precursor molecules that are cleaved at a conserved RXXR motif into the mature C-terminal dimer and the N-terminal proregion; binding of the ligand by the N-terminal remnant results in a biologically inactive latent complex. This requirement for activation of …