Mini review The therapeutic potential of blocking the activin signalling pathway Francesco Elia Marino a , Gail Risbridger b , Elspeth Gold a, * a Department of Anatomy, University of Otago, Dunedin, New Zealand b Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia 1. Introduction: TGF-b and tissue homeostasis Normal homeostasis in human tissues requires a complex and balanced interaction between cells and the network of secreted protein known as the extracellular matrix. These interactions involve the action of numerous cytokines and growth factors through specific cell-surface receptors. When the balance between these cells and the extracellular matrix is disrupted, disease can result. In particular, growth factors regulate a plethora of biological process modulating or orchestrating the developmental pro- gramme, growth and differentiation profile and maintaining physiological conditions in most cell types [1]. The first part of this review will focus on the mechanism by which TGF-b mediates its cellular function, focusing on its role in disease. The second part of the review will outline the importance of the activin pathway focusing on the correlation with gonadal tumours and cancer associated cachexia, finally presenting an overview of the main therapeutic strategies used recently to antagonise activin signalling. 1.1. TGF-b superfamily protein networks and its signalling TGF-b1 is a member of a family of dimeric poly-peptide growth factors that includes bone morphogenic proteins (BMP), activins, inhibins, nodal and growth differentiation factors (GDF). All these growth factors share a cluster of conserved cysteine residues that form a common cysteine knot structure held together by disulphide bonds [2]. Virtually, every cell in the body produces TGF-b1 and has receptors for it. The essential role of TGF-b in the regulation of proliferation, differentiation, embryonic develop- ment, wound healing and angiogenesis has been demonstrated by targeted deletion of the genes encoding members of this pathway in mice [3]. TGF-b1 itself inhibits proliferation of many cell types, and its signalling controls tumourigenesis. The cell’s responses to TGF-b1 are complex as a result of differential transcriptional regulation and non-transcriptional effects that depend on the cell context and physiological environment [4]. The current model of induction of signalling response by TGF-b’s factor is a linear signalling pathway from the type II to the type I receptor kinase to Smad activation resulting in a final event of transcriptional activation [5]. Interestingly this pathway presents versatility in receptors interactions and ligand binding and additionally receptor activation can induce the non-Smad signalling pathways that in turn can regulate Smad signalling or lead to Smad independent responses [6]. The TGF-b family of receptors consists of two ‘‘type II’’ and two ‘‘type I’’ trans membrane serine/threonine kinase receptor sub- units [7]. These receptors are structurally the same but the type I receptor has a Glycine–Serine-rich ‘‘GS sequence’’ immediately upstream from the kinase domain. Binding of ligand to the receptors allows the formation of a stable receptor complex consisting of two receptors of each type; this leads to the phosphorylation of the GS sequences by the type II receptor Cytokine & Growth Factor Reviews xxx (2013) xxx–xxx A R T I C L E I N F O Article history: Available online xxx Keywords: TGF-b TGF-b antagonism Activin antagonism Cancer associated cachexia A B S T R A C T Members of the transforming growth factor b (TGF-b) family regulate fundamental physiological process, such as cell growth, differentiation and apoptosis. As a result, defects in this pathway have been linked to uncontrolled proliferation and cancer progression. Here we explore the signal transduction mechanism of TGF-b focusing on therapeutic intervention in human diseases. Like TGF-b, another member of the TGF-b superfamily, activin has been proven to play an important role in maintenance of tissue homeostasis and dysregulation leads to disease. Several studies showed elevated levels of activin are responsible for the development of gonadal tumours and a cachexia-like weight loss syndrome. Discussing the recent advances in approaches developed to antagonise the activin pathway and the encouraging results obtained in animal models, this review presents a therapeutic rationale for targeting the activin pathway in conditions such as cachexia, neuromuscular and/or musculoskeletal disorders. ß 2013 Elsevier Ltd. All rights reserved. * Corresponding author at: Department of Anatomy, University of Otago, PO Box 913, Dunedin 9054, New Zealand. Tel.: +64 3 479 5647; fax: +64 3 479 7254. E-mail addresses: marfr063@student.otago.ac.nz (F.E. Marino), elspeth.gold@otago.ac.nz (E. Gold). G Model CGFR-731; No. of Pages 8 Please cite this article in press as: Marino FE, et al. The therapeutic potential of blocking the activin signalling pathway. Cytokine Growth Factor Rev (2013), http://dx.doi.org/10.1016/j.cytogfr.2013.04.006 Contents lists available at SciVerse ScienceDirect Cytokine & Growth Factor Reviews jo ur n al ho mep ag e: www .elsevier .c om /loc ate/c yto g fr 1359-6101/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2013.04.006