The TGFβ signaling system affects many aspects of life, from embryogenesis to congenital and chronic disease, to tissue repair and homeostasis in adult animals. At the cellular level, this all-embracing system regulates cell proliferation and differentiation, survival and apoptosis,migration and intercalation, adhesion, and matrix production and interaction. Developmental biologists want to identify and functionally characterize the many components of the TGFβ system that make cells change their fate and differentiate in embryos and their organs. Altogether, the field has identified many ligand-encoding genes (33 in the human genome), a few receptors (seven type-I and five type-II receptors) and a few receptor-activated Smads (Smads 1, 2, 3, 5, 8), one co-Smad (Smad4) and two inhibitory Smads (Smads 6, 7), many Smad-interacting proteins (SIPs; I stopped counting at 120 two years ago) and still too few direct target genes. With the identification of the Smads as intracellular effector proteins of TGFβreceptor signaling in the mid-90s, the rapid progress and the enormous diversification of the Smad field, as witnessed by the 2,717 hits in a literature database search for Smad at the time of writing this review, time is indeed right to move from the many review articles on Smads to a reasonably comprehensive and accessible text. This text would ideally gather all relevant information on Smads in signal transduction in general and at the crossroads between developmental and cell biology in particular. This is what the book, Smad Signal Transduction: Smads in Proliferation, Differentiation and Disease, edited by Peter ten Dijke and Carl-Henrik Heldin, aspires to do,but does not always achieve.FIG1
The editors of this book have, however, firmly set themselves an ambitious goal. In 22 chapters (preceded by a preface from the editors) and in 459 pages of text, different researchers in the field cover various fundamental aspects of Smad biology. These include their activities in different processes, their intracellular trafficking, structure-function and evolutionary relationship,post-translational modifications, non-Smad partners, cross-signaling with other systems, novel high-throughput and computational approaches, and their role in disease. Each is a stand-alone chapter, in most cases compiled by one team; about a quarter of the chapters are written by co-authors from different institutes or organizations and, therefore, provide a well-integrated view of a particular aspect of Smad biology. A certain amount of redundancy is present between some chapters, but not to a distracting degree.
In the preface, the editors start by rightly emphasizing the enormously important contributions of Drosophila and Caenorhabditis elegans genetics to this field, which led to the identification of the Mad and sma genes, respectively, that encode Smad proteins. This justifies the incorporation into the book of chapters on the molecular evolution of Smad proteins (Chapter 1) and Smad signaling in C. elegans (Chapter 2) and Drosophila (Chapter 3). The focus in Chapter 1 is on receptor-activated Smads in humans, Drosophila and C. elegans, and not only provides a table that summarizes Smad nomenclature in different species, but also discusses evolutionary relationships at the level of the Smad domains. The trained zoologist in me missed having an update on the recent progress in Hydra and jellyfish(both coelenterates), and in Ciona (or any other ascidian as representative of the urochordates). Chapter 2 provides an overview of nematode Smad pathways, and includes interesting views on body size regulation by TGFβ components, including Sno/Ski-like proteins, and a brief discussion of the non-involvement of TGFβ signaling in the control of the dorsal-ventral axis in nematodes, in contrast to Drosophila and vertebrates. Chapter 3 incorporates more developmental biology, as it discusses, among other things, how Smads contribute to graded bone morphogenetic protein (BMP) signaling, and how Schnurri and Brinker cooperate in the Smad pathway. It also critically notes that the specificity of the Smad proteins Mad and Smox for BMP and activin receptors, respectively, has never actually been tested in vivo.
The next four chapters take the reader on a tour of the role(s) of Smads in different ligand-controlled cellular processes, such as in the arrest or stimulation of cell cycle progression and cell proliferation (Chapter 4), in the stimulation or inhibition of mesenchymal differentiation (Chapter 5), in apoptosis versus survival (Chapter 6), and in epithelial-to-mesenchymal transition (EMT) and vice versa (MET) (Chapter 7). In all of these chapters,the two `faces' of the TGFβ-Smad system are clearly visible, as its signaling can elicit opposite effects depending on the players and/or the cellular context. For the developmental biologist, the content of these chapters somehow suffers from the fact that much of the initial work is inherently linked to cell culture. A chapter on the role of TGFβsignaling in hematopoiesis or in heart development (to name but a few) would have been equally welcome. Chapter 5, however, does present a very nice picture of the mechanisms through which BMP-activated Smads promote, and TGFβ-activated Smad3 inhibits, osteoblast differentiation. It then compares this with adipocyte, chondrocyte and myocyte differentiation. Similarly, Chapter 7 gives a coherent and critical view of the role of Smad and non-Smad signaling in EMT/MET, which are studied both in vitro and in vivo. I appreciated very much the compilation in Chapter 8 of the currently available mouse models for studying Smads in development, disease and cancer. The time is indeed ripe to update this list and also the conclusions that can be drawn from conventional and tissue-specific Smad knockouts and double knockouts. However, the conditional mouse models discussed in this chapter are mainly ones in which gene function has been altered or abrogated in adult tissue or in relation to cancer rather than to embryogenesis.
This is definitely an `all-in' book... a must for all of us working in the field of TGFβ signaling and Smad signal transduction
The book then moves into more cell biological studies of the connection between the endocytic routing of receptors and Smad activation (Chapter 9) and the nuclear import and export of Smads (Chapter 10). Both of these processes contribute to the regulation of Smad availability and/or activity. Endocytosis does not exclusively serve to downregulate ligand-bound receptors, but is also crucial for the spatial and temporal regulation of Smad activation. Depending on the endocytic route taken (the best-studied are clathrin-mediated endocytosis towards early endosomes and the caveolar route to the caveosome),the cell responds differently, at least in cell culture. Unfortunately, the authors of this chapter, Christine Le Roy, Rohit Bose and Jeffrey Wrana, have not included recent findings that BMP receptor complexes not only assemble in different ways, but also that their differential routing can determine Smad versus non-Smad signaling. Recent insights (from the group of Eddy de Robertis) into the role of BMP-Smad linker-domain phosphorylation in the subcellular distribution of Smad proteins will be an appropriate addition to Chapter 10 in a future edition of this book. In addition to receptor endocytosis, the post-translational modification of Smads by phosphorylation(discussed in Chapter 12) and by ubiquitylation and sumoylation (covered in Chapter 13) also regulate Smad activation and functions. These two chapters provide an excellent entry into this rapidly evolving subfield.
Chapter 11, on the structure-function relationship of receptor-activated Smad proteins, is one of the best I have read in the field. It is excellently written and, as you might expect, excellently structured. The content of the chapter is timeless and will be a very important reference text for many of us in the future.
One of the nearly impossible tasks the authors, Kohei Miyazono, Shingo Maeda and Takeshi Imamura, faced was that of giving a comprehensive review of the Smad transcriptional partners. However, they succeeded in doing so in Chapter 14 by structuring this vast amount of information into sections on Smad complex-induced transcriptional activation and repression, respectively,and by their focus on the well-studied players. A concise introduction to the role of chromatin modulation itself would have been useful here, as would a discussion of the function(s) of multi-domain SIPs when they are not bound to Smad(s). The next chapter truly enforces the - sometimes fatalistic - view that TGFβ signaling has really been invented to interfere, or more diplomatically, to cross-signal, with many other signaling systems. How TGFβ signaling integrates with Wnt, Notch, Hedgehog, Jak/Stat, nuclear hormone receptor, NF-κB, HIF1 (hypoxia), p53, PKA and non-receptor kinases, is all compiled here. However, much of this work remains to be put into a physiological context. Similarly, the content of Chapters 15 and 16(which covers the integration of Smad and MAP kinase pathways) is likely to be subject to rapid change.
The discussion of high-throughput or systems-based approaches for investigating TGFβ signaling comes with important words of caution from Erwin Böttinger and Wenjun Ju, and from Muneesh Tewari and Arvind Rao,the authors of Chapters 17 and 18, respectively. There is no doubt that a Smad protein can act as a true node in a signaling network, but much of this work is still descriptive and without quantitative predictions of system behavior if one of the TGFβ components is removed or downregulated. Finally, the remaining chapters discuss disease, notably the role of inhibitory Smads in human disease (Chapter 19), and the association of altered Smad signaling with carcinogenesis (Chapter 20). This chapter also provides a status report on the use of TGFβ receptor kinase inhibitors for cancer and fibrosis therapy.
This is definitely an `all-in' book for those interested in or working on TGFβ receptor signal transduction in general and Smad proteins in particular. It will not entirely satisfy the developmental biologist, but it may well have not aimed to do so. However, it is a must for all of us working in the field of TGFβ signaling and Smad signal transduction, and for those of us who are teaching post-graduate courses in signal transduction. An important feature of this book, in this regard, is that many of its figures are available in color on an accompanying website.