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Smad linker region phosphorylation in the regulation of extracellular matrix synthesis

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Abstract

The canonical TGF-β signalling pathway involves Smad transcription factors through direct serine phosphorylation of the carboxy termini, nuclear translocation and regulation of transcription by receptor-regulated (R)-Smad complexes. Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (MAP) kinases, which in turn have been activated by TGF-β or a multitude of other growth factors and hormones. Linker region phosphorylation can prevent nuclear translocation of Smads and inhibit TGF-β signalling, potentially leading to oncogenesis. However, some evidence has revealed that linker region phosphorylated Smads can be translocated to the nucleus where they regulate transcription particularly of the synthesis of extracellular matrix molecules. Matrix molecules such as collagen and proteoglycans are involved in diseases such a fibrosis and atherosclerosis, respectively, and the involvement of linker region phosphorylation may represent a new therapeutic target.

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Acknowledgments

This study was supported by a National Health and Medical Research Council of Australia Fellowship (P.J.L.) and a National Heart Foundation of Australia grant-in-aid (P.J.L.) and Diabetes Australia Research Trust grants (P.J.L. and N.O.). The Ph.D. program of M.L.B. generously received support through a National Heart Foundation of Australia post-graduate scholarship and a post-graduate support award from GlaxoSmithKline Australia to P.J.L. W.Z. acknowledges support from the National Natural Science Fund of China (no. 30670652; no. 30711120565; no. 30970935).

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Authors and Affiliations

  1. Diabetes and Cell Biology Laboratory, BakerIDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia

    Micah L. Burch & Peter J. Little

  2. Departments of Medicine and Immunology, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health), Prahran, VIC, 3004, Australia

    Micah L. Burch & Peter J. Little

  3. School of Pharmaceutical Sciences, Sun Yat-Sen University, 510080, Guangzhou, Guangdong, China

    Wenhua Zheng

  4. St. Kilda Rd Central, PO Box 6492, Melbourne, VIC, 8008, Australia

    Peter J. Little

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Correspondence to Peter J. Little.

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Burch, M.L., Zheng, W. & Little, P.J. Smad linker region phosphorylation in the regulation of extracellular matrix synthesis. Cell. Mol. Life Sci. 68, 97–107 (2011). https://doi.org/10.1007/s00018-010-0514-4

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