209 10.2217/FNL.12.3 © 2012 Future Medicine Ltd ISSN 1479-6708 Future Neurol. (2012) 7(2), 209–224 part of Future Neurology TGF-b signaling The TGF-b superfamily consists of 33 secreted cytokines in humans, which include TGF-β-1, -2, -3, BMPs, growth and differentiation fac- tors (GDFs), activins/inhibins and nodal-related proteins [1,2] . Most of these members are synthe- sized as latent proteins, which are proteolytically cleaved for activation and form functional dimers that initiate downstream signaling through spe- cific receptor interactions. These dimeric ligands bind and assemble heterotetrameric complexes of two types of transmembrane serine/threo- nine kinase receptors, designated as the type I and type II receptors. Five type II receptors, namely Activin receptor IIA and IIB (ACVR2A, ACVR2B), TGF-β receptor II (TGFBR2), BMP receptor II (BMPR2), Müllerian inhibiting sub- stance receptor II (MISR2) and seven type I receptors, which are termed activin receptor- like kinases (ALK 1–7, see TABLE 1 for official gene symbols) have been identified with differ- ent combinations of type I/II receptors medi- ating the activity of different family members proteins (TABLE 1) [1,2] . Activin initiates signaling by binding to ACVR2A/B, in combination with type 1 receptors ALK4 and ALK7. TGF-β itself mainly uses TGFBR2 and ALK5, with an exception in endothelial cells in which it can signal via ALK1. Similar to activin, myostatin (also known as GDF-8), can bind to ACVR2A, ACVR2B and ALK4, but is also able to signal via ALK5 [3,4] . BMP ligands form complexes with other receptor combinations, namely the type II receptors BMPR2 or ACVR2A/B with type I receptors ALK1, ALK2, ALK3 and ALK6 [2] . Ligand–receptor complex formation leads to activation of the type I receptor through type II receptor-mediated phosphorylation of serine and threonine residues in the GS domain. The acti- vated type I receptor will subsequently phospho- rylate the intracellular receptor-regulated Smad (R-Smad) proteins. Upon association of R-Smads with the common Smad protein (Smad4), the heteromeric Smad complexes translocate into the nucleus, where they regulate the transcription of a multitude of target genes. Different R-Smads are activated by different ligands, with activin, TGF-β and myostatin signaling being mediated via Smad2 and Smad3, and BMP signaling via Smad1/5/8 (FIGURE 1) [1] . In addition to the combination of type I/II receptors, the TGF-β signaling pathways are further fine-tuned at multiple levels, for exam- ple by presence of extracellular antagonists that modify ligand activity and availability [5] . Furthermore, several co-receptors can either increase or decrease the affinity of ligands for type I/II receptor binding. Tissue specificity of the TGF-β family is also achieved by spatio-tem- poral expression of these modulatory proteins. An overview of TGF-β family members, their receptors, co-receptors and interacting proteins is presented in TABLE 1. Role of TGF-b signaling in adult skeletal muscle regeneration & regulation of muscle mass Postnatal skeletal muscle growth and matura- tion occurs due to the activity of the muscle pro- genitor cells, called satellite cells, which have the TGF-b signaling in Duchenne muscular dystrophy Dwi U Kemaladewi 1,2 , Peter A ‘t Hoen 1 , Peter ten Dijke 2 , Gert Jan van Ommen 1 & Willem M Hoogaars* 1 1 Department of Human Genetics, Leiden University Medical Center, Postzone S4-P, PO Box 9600 2300RC Leiden, The Netherlands 2 Department of Molecular & Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postzone S4-P, PO Box 9600 2300RC Leiden, The Netherlands *Author for correspondence: n Tel.: +31 71 5269420 n Fax: +31 71 5268285 n w.m.h.hoogaars@lumc.nl The TGF- b protein family consists of secreted multifunctional cytokines that control diverse processes, such as cell growth and differentiation. Aberrant expression and downstream signaling of these growth factors have been associated with multiple diseases, including muscle wasting disorders, such as Duchenne muscular dystrophy. In this review we discuss recent advances in understanding the role of TGF- b family members during normal skeletal muscle biology/regeneration and their role in muscle pathology, with a special focus on Duchenne muscular dystrophy. In addition, we will highlight progress in the development of potential therapeutics for Duchenne muscular dystrophy based on intervention of TGF- b signaling. Keywords n activin n BMP n DMD n fibrosis n muscle regeneration n myostatin n TGF-b Review For reprint orders, please contact: reprints@futuremedicine.com