Table of Contents
Jan 2009
Volume 19, Issue 1, Page 1-148
About the Cover:  
Ye-Guang Chen1 and Xiao-Fan Wang2
Cell Research (2009) 19:1-2. doi: 10.1038/cr.2009.3; published online 5 January 2009
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Tetsuo Tsuchida, Taro Kawai and Shizuo Akira
Cell Research (2009) 19:3-4. doi: 10.1038/cr.2009.1; published online 5 January 2009
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Xiaomeng Zhang1,3, Helena E Richardson2,4 and Kieran F Harvey1,3
Cell Research (2009) 19:5-7. doi: 10.1038/cr.2009.2; published online 5 January 2009
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Katharine H Wrighton, Xia Lin1 and Xin-Hua Feng
Cell Research (2009) 19:1-2. doi: 10.1038/cr.2009.3; published online 5 January 2009
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Members of the transforming growth factor-β (TGF-β) family control a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. Thus, aberrant TGF-β signaling can play a key role in the pathogenesis of several diseases, including cancer. TGF-β signaling pathways are activated by a short phospho-cascade, from receptor phosphorylation to the subsequent phosphorylation and activation of downstream signal transducers called R-Smads. R-Smad phosphorylation state determines Smad complex assembly/disassembly, nuclear import/export, transcriptional activity and stability, and is thus the most critical event in TGF-β signaling. Dephosphorylation of R-Smads by specific phosphatases prevents or terminates TGF-β signaling, highlighting the need to consider Smad (de)phosphorylation as a tightly controlled and dynamic event. This article illustrates the essential roles of reversible phosphorylation in controlling the strength and duration of TGF-β signaling and the ensuing physiological responses.
Peter Lönn, Anita Morén, Erna Raja, Markus Dahl and Aristidis Moustakas
Cell Research (2009) 19:21-35. doi: 10.1038/cr.2008.308; published online 25 November 2008
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Transforming growth factor β (TGFβ) controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight links between these mechanisms and human diseases, such as tissue fibrosis and cancer.
Caroline S Hill
Cell Research (2009) 19:36-46. doi: 10.1038/cr.2008.325; published online 30 December 2008
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Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β (TGF-β)-superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-β-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-β-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-β superfamily members is discussed.
Julien Deheuninck and Kunxin Luo
Cell Research (2009) 19:47-57. doi: 10.1038/cr.2008.324; published online 30 December 2008
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Ski and the closely related SnoN were discovered as oncogenes by their ability to transform chicken embryo fibroblasts upon overexpression. While elevated expressions of Ski and SnoN have also been reported in many human cancer cells and tissues, consistent with their pro-oncogenic activity, emerging evidence also suggests a potential anti-oncogenic activity for both. In addition, Ski and SnoN have been implicated in regulation of cell differentiation, especially in the muscle and neuronal lineages. Multiple cellular partners of Ski and SnoN have been identified in an effort to understand the molecular mechanisms underlying the complex roles of Ski and SnoN. In this review, we summarize recent findings on the biological functions of Ski and SnoN, their mechanisms of action and how their levels of expression are regulated.
Ye-Guang Chen
Cell Research (2009) 19:58-70. doi: 10.1038/cr.2008.315; published online 2 December 2008
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Transforming growth factor-β (TGF-β) signaling is tightly regulated to ensure its proper physiological functions in different cells and tissues. Like other cell surface receptors, TGF-β receptors are internalized into the cell, and this process plays an important regulatory role in TGF-β signaling. It is well documented that TGF-β receptors are endocytosed via clathrin-coated vesicles as TGF-β endocytosis can be blocked by potassium depletion and the GTPase-deficient dynamin K44A mutant. TGF-β receptors may also enter cells via cholesterol-rich membrane microdomain lipid rafts/caveolae and are found in caveolin-1-positive vesicles. Although receptor endocytosis is not essential for TGF-β signaling, clathrin-mediated endocytosis has been shown to promote TGF-β-induced Smad activation and transcriptional responses. Lipid rafts/caveolae are widely regarded as signaling centers for G protein-coupled receptors and tyrosine kinase receptors, but they are indicated to facilitate the degradation of TGF-β receptors and therefore turnoff of TGF-β signaling. This review summarizes current understanding of TGF-β receptor endocytosis, the possible mechanisms underlying this process, and the role of endocytosis in modulation of TGF-β signaling.
Xing Guo* and Xiao-Fan Wang
Cell Research (2009) 19:71-88. doi: 10.1038/cr.2008.302; published online 11 November 2008
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Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of all metazoans. Deregulation of TGF-β/BMP activity almost invariably leads to developmental defects and/or diseases, including cancer. The proper functioning of the TGF-β/BMP pathway depends on its constitutive and extensive communication with other signaling pathways, leading to synergistic or antagonistic effects and eventually desirable biological outcomes. The nature of such signaling cross-talk is overwhelmingly complex and highly context-dependent. Here we review the different modes of cross-talk between TGF-β/BMP and the signaling pathways of Mitogen-activated protein kinase, phosphatidylinositol-3 kinase/Akt, Wnt, Hedgehog, Notch, and the interleukin/interferon-gamma/tumor necrosis factor-alpha cytokines, with an emphasis on the underlying molecular mechanisms.
David Padua and Joan Massagué
Cell Research (2009) 19:89-102. doi: 10.1038/cr.2008.316; published online December 2008
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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in pre-clinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.
Tetsuro Watabe and Kohei Miyazono
Cell Research (2009) 19:103-115. doi: 10.1038/cr.2008.323; published online 30 December 2008
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Transforming growth factor (TGF)-βs and their family members, including bone morphogenetic proteins (BMPs), Nodal and activins, have been implicated in the development and maintenance of various organs, in which stem cells play important roles. Stem cells are characterized by their ability to self-renew and to generate differentiated cells of a particular tissue, and are classified into embryonic and somatic stem cells. Embryonic stem (ES) cells self-renew indefinitely and contribute to derivatives of all three primary germ layers. In contrast, somatic stem cells, which can be identified in various adult organs, exhibit limited abilities for self-renewal and differentiation in most cases. The multi-lineage differentiation capacity of ES cells and somatic stem cells has opened possibilities for cell replacement therapies for genetic, malignant and degenerative diseases. In order to utilize stem cells for therapeutic applications, it is essential to understand the extrinsic and intrinsic factors regulating self-renewal and differentiation of stem cells. More recently, induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts that resemble ES cells via ectopic expression of four transcription factors. iPS cells may have an advantage in regenerative medicine, since they overcome the immunogenicity and ethical controversy of ES cells. Moreover, recent studies have highlighted the involvement of cancer stem cells during the formation and progression of various types of cancers, including leukemia, glioma, and breast cancer. Here, we illustrate the roles of TGF-β family members in the maintenance and differentiation of ES cells, somatic stem cells, and cancer stem cells.
Marie-José Goumans, Zhen Liu and Peter ten Dijke
Cell Research (2009) 19:116-127. doi: 10.1038/cr.2008.326; published online 30 December 2008
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Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.
Ying E Zhang
Cell Research (2009) 19:128-139. doi: 10.1038/cr.2008.328; published online 30 December 2008
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Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.
Yao-Yun Liang, F Charles Brunicardi and Xia Lin
Cell Research (2009) 19:140-148. doi: 10.1038/cr.2008.321; published online 16 December 2008
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Id1 is a member of the inhibitor of differentiation (Id) protein family that regulates a wide range of cell functions. Previous studies have shown that expression of the Id1 gene is down-regulated by TGF-β in epithelial cells, whereas it is up-regulated by BMP in a variety of cell types. During our study of the biological function of TGF-β1, we found that Id1 can be strongly up-regulated by TGF-β1 in the human mammary gland epithelial cell line MCF10A. Quantitative real-time RT-PCR has revealed as high as 7.5-fold induction of Id1 mRNA by TGF-β1 in MCF10A cells after 1 h of TGF-β1 stimulation, and this induction does not require de novo protein synthesis. Using Smad knockdown and knockout approaches, we have identified Smad3 as the responsible R-Smad for mediating transcriptional activation of the Id1 gene. Chromatin immunoprecipitation assay confirms that Smad3 and Smad4 bind to the upstream region of the Id1 gene. Our results demonstrate that Smad3, but not Smad2, mediates TGF-β1-dependent early transcriptional induction of Id1.



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