14 Non-Smad TGF-β Signaling Pathways

Abstract

TGF-β and related factors, including activin and bone morphogenetic proteins (BMPs), exert diverse effects on a wide array of cellular processes ranging from proliferation and differentiation to apoptosis. For example, TGF-β itself is well established as a potent growth inhibitor for cells of epithelial origin through its ability to induce cell cycle arrest in late G₁ and to promote an apoptotic response, as reviewed in Chapter 11. TGF-β is also a key regulator of epithelial–mesenchymal transdifferentiation, a process known for promoting tumor invasion and metastasis and involving dissociation of tight junctions, reorganization of the actin cytoskeleton, and induction of mesenchymal gene expression, as discussed in Chapter 29. At the cell surface, this plethora of signaling functions of the TGF-β family is mediated by a heteromeric complex of two types of transmembrane receptors, each equipped with an intracellular serine-threonine kinase domain. Binding of ligands to the receptor complex leads to phosphorylation and thereby activation of the type I receptor by the type II receptor kinase (Chapters 6 and 9). However, downstream from this focal point, the uniformity ends; depending on the cellular context and the process that it regulates, the activated receptor complex relays the signal through multiple intracellular pathways. In the Smad pathway, the activated type I receptor phosphorylates receptor-activated Smads (R-Smads); for example, Smad2 and Smad3 in response to TGF-β, or Smad1, Smad5, and Smad8 in response to BMP signaling. The specificity of a type I receptor kinase toward R-Smads is determined by the L45 loop between kinase...