Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-β signalling

  • Danielle KamatoEmail author
  • Bich Hang Do
  • Narin Osman
  • Benjamin P. Ross
  • Raafat Mohamed
  • Suowen Xu
  • Peter J. Little


Transforming growth factor (TGF)-β signalling pathways are intensively investigated because of their diverse association with physiological and pathophysiological states. Smad transcription factors are the key mediators of TGF-β signalling. Smads can be directly phosphorylated in the carboxy terminal by the TGF-β receptor or in the linker region via multiple intermediate serine/threonine kinases. Growth factors in addition to hormones and TGF-β can activate many of the same kinases which can phosphorylate the Smad linker region. Historically, Smad linker region phosphorylation was shown to prevent nuclear translocation of Smads and inhibit TGF-β signalling pathways; however, it was subsequently shown that Smad linker region phosphorylation can be a driver of gene expression. This review will cover the signalling pathways of Smad linker region phosphorylation that drive the expression of genes involved in pathology and pathophysiology. The role of Smad signalling in cell biology is expanding rapidly beyond its role in TGF-β signalling and many signalling paradigms need to be re-evaluated in terms of Smad involvement.


Nuclear translocation G protein coupled receptors Serine/threonine kinase receptors Cancer Alk 5 Cell signalling 



Bone morphogenetic proteins


Chondroitin 4-O-sulfotransferase 1


Chondroitin synthase 1


Epidermal growth factor


Epidermal growth factor receptor




G protein-coupled receptor


Matrix metalloproteinase


Plasminogen activator inhibitor-1


Protease-activated receptor


Platelet-derived growth factor


Protein tyrosine kinase receptor


Serine/threonine kinase receptor


Transforming growth factor-β receptor type 1


Transforming growth factor-β


Vascular smooth muscle cells



DK was supported by the NHMRC (APP1160925) and National Heart Foundation Fellowship (102129). Support was received from the University of Queensland through a personal support package to PJL and by the University of Queensland Early Career Grant (DK) (Grant no. 1832825).


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Pharmacy Australia Centre of Excellence, School of PharmacyThe University of QueenslandWoolloongabbaAustralia
  2. 2.Department of PharmacyXinhua College of Sun Yat-Sen UniversityGuangzhouChina
  3. 3.Faculty of PharmacyTon Duc Thang UniversityHo Chi Minh CityVietnam
  4. 4.School of Medical SciencesRMIT UniversityBundooraAustralia
  5. 5.Department of ImmunologyMonash UniversityMelbourneAustralia
  6. 6.Department of Medicine, Aab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterUSA
  7. 7.Department of Basic Sciences, College of DentistryUniversity of MosulMosulIraq

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