LAUSR

The transforming growth factor-β (TGF-β) family of ligands comprises 33 members in humans, of which 30 are positively acting ligands including the TGF-βs, the Activins, the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs) and antiMullerian hormone, and 3 are ligand antagonists: inhibin-α (INHA), LEFTY1, and LEFTY2. This ligand family has been evolutionarily conserved from simple placozoa like Trichoplax to humans. They play crucial roles in early embryonic development in both vertebrates and invertebrates and are essential for germ layer specification and tissue patterning. They are also required for maintaining tissue homeostasis in adults, playing key regulatory roles in virtually every organ of the body. As a result of these functions, deregulated TGF-β family signaling can cause many serious human diseases and syndromes. The receptors for these ligands are serine/ threonine kinases, and two distinct receptors are required for signaling, type I and type II. In addition, many ligands require additional co-receptors. The signals from these receptors are predominantly transduced from the plasma membrane to the nucleus by the SMAD proteins (homologues of C. elegans SMA, and Drosophila MAD proteins, although a number of other non-SMAD signaling pathways can also be activated in different contexts. This Special Issue contains a diverse selection of articles that explore some of the basic mechanisms of TGF-β family signaling, the roles of these ligands in embryonic development, and, finally, the underlying mechanisms whereby deregulated signaling results in human disease. The papers included in this issue can be identified as belonging to three distinct categories as described below: The first clutch of papers in this issue concerns new insights into the fundamental principles of TGF-β family signaling. Beginning with the ligands, Rifkin et al. discuss the latent TGF-β binding proteins (LTBPs) with respect to their role in regulating TGF-β ligand activity. All TGF-β family proteins are synthesized as long precursors, with an N-terminal prodomain and a C-terminal mature domain, separated by a furin cleavage site. The mature domains constitute the active ligand and act as dimers. The ligands are cleaved during secretion, but in some cases the prodomains stay associated with the mature domains. In the case of the TGF-β ligands, the mature domain is enveloped by the prodomain to generate what is called the latent complex. The ligand must be released from this complex to be able to signal—a process referred to as ligand activation. The LTBPs, with the exception of LTBP2, bind to the TGF-β prodomain via a disulfide linkage, assisting with ligand secretion and sequestering the latent TGF-β complex to the extracellular matrix (ECM). Rifkin et al. review the evidence for the function of the LTBPs in TGF-β activation, and go on to discuss the phenotypes of LTBP1-4 null mice, relating these phenotypes to human diseases arising from mutations in these proteins. They also address unanswered questions in the field, including the function of other latent TGF-β binding proteins, the role of the long and short forms of LTBPs, and the issues of specificity of binding between different LTBPs and the different TGFβs. Moving from ligands to receptors, the next review by Pawlak and Blobe focuses on the wide range of coreceptors that modulate signaling by TGF-β family ligands. They focus on nine of these co-receptors, which between them affect the activity of the TGF-βs, Activin, Nodal, and BMPs. These co-receptors are membrane bound, but many also exist as soluble forms that can antagonize the membrane-associated form. Pawlak and Blobe explore the role of these co-receptors in normal physiological signaling and also in deregulated signaling in cancer. They finish with a discussion of pharmacological targeting of these co-receptors for therapeutic ends. Goodman and Savage-Dunn then discuss reciprocal interactions between TGF-β signaling and components of the ECM, in particular, collagens, from the perspective of the nematode, Caenorhabditis elegans. This organism has historically been crucial for unraveling the mechanism of TGF-β family signaling. The authors review the evidence for bidirectional interactions between TGF-β signaling and the ECM in C. elegans. This includes how molting, wounding, and infection impact TGF-β signaling, the regulation of collagen gene expression by TGF-β signaling, and feedback regulation of TGF-β signaling by the cuticle. They end with a discussion of C. elegans body size regulation. Body size itself is regulated by integration of target of rapamycin, BMP, and insulin signaling, with DOI: 10.1002/dvdy.445