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Open Access Highly Accessed Review

Activin signaling as an emerging target for therapeutic interventions

Kunihiro Tsuchida1*, Masashi Nakatani1, Keisuke Hitachi1, Akiyoshi Uezumi1, Yoshihide Sunada2, Hiroshi Ageta13 and Kaoru Inokuchi34

Author Affiliations

1 Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan

2 Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan

3 Mitsubishi Kagaku Institute of Life Sciences, MITILS, 11 Minamiooya, Machida, Tokyo 194-8511, Japan

4 Japan Science and Technology Agency, CREST, Kawaguchi, Saitama 332-0012, Japan

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Cell Communication and Signaling 2009, 7:15  doi:10.1186/1478-811X-7-15

Published: 18 June 2009

Abstract

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands.

The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.