Review

Cellular and Molecular Life Sciences

, Volume 68, Issue 1, pp 97-107

First online:

Smad linker region phosphorylation in the regulation of extracellular matrix synthesis

  • Micah L. BurchAffiliated withDiabetes and Cell Biology Laboratory, BakerIDI Heart and Diabetes InstituteDepartments of Medicine and Immunology, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health)
  • , Wenhua ZhengAffiliated withSchool of Pharmaceutical Sciences, Sun Yat-Sen University
  • , Peter J. LittleAffiliated withDiabetes and Cell Biology Laboratory, BakerIDI Heart and Diabetes InstituteDepartments of Medicine and Immunology, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health) Email author 

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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.

Keywords

Transforming growth factor-β Smads Phosphorylation Signalling Vascular smooth muscle Collagen Proteoglycans