Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-β mediates diverse biological responses by signalling through type I and II TGF-β receptors (TβRI and TβRII). We have previously identified CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, as a novel TGF-β co-receptor that negatively regulates TGF-β signalling and responses and demonstrated that membrane-anchored CD109 promotes TGF-β receptor degradation via a SMAD7/Smurf2-mediated mechanism. To determine whether CD109 released from the cell surface (soluble CD109 or sCD109) also acts as a TGF-β antagonist, we determined the efficacy of recombinant sCD109 to interact with TGF-β and inhibit TGF-β signalling and responses. Our results demonstrate that sCD109 binds TGF-β with high affinity as determined by surface plasmon resonance (SPR) and cell-based radioligand binding and affinity labelling competition assays. SPR detected slow dissociation kinetics between sCD109 and TGF-β at low concentrations, indicating a stable and effective interaction. In addition, sCD109 antagonizes TGF-β-induced Smad2/3 phosphorylation, transcription and cell migration. Together, our results suggest that sCD109 can bind TGF-β, inhibit TGF-β binding to its receptors and decrease TGF-β signalling and TGF-β-induced cellular responses.
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Structure of the alpha1, beta1, gamma1 isoform of AMPK bound to a chlorinated analog of A769662 (‘Cl-A769662’). Alpha colored in purple, beta in blue, gamma in light pink. Cl-A769662 shown in yellow sticks and AMP bound to gamma shown in green sticks. Image kindly provided by Francis Rajamohan (Groton, U.S.A.). - PDF Icon PDF LinkFront Matter
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Research Article|
February 24 2016
Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses
Carter Li;
Carter Li
*Division of Plastic Surgery, Department of Surgery, McGill University Health Centre, Montreal, QC, Canada, H3G1A4
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Mark A. Hancock;
Mark A. Hancock
†McGill SPR-MS Facility, McGill University, Montreal, QC, Canada, H3A 2B4
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Priyanka Sehgal;
Priyanka Sehgal
*Division of Plastic Surgery, Department of Surgery, McGill University Health Centre, Montreal, QC, Canada, H3G1A4
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Shufeng Zhou;
Shufeng Zhou
*Division of Plastic Surgery, Department of Surgery, McGill University Health Centre, Montreal, QC, Canada, H3G1A4
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Dieter P. Reinhardt;
Dieter P. Reinhardt
‡Department of Anatomy and Cell Biology, Faculty of Medicine and Faculty of Dentistry, McGill University, Montreal, QC, Canada, H3A 0C7
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Anie Philip
Anie Philip
1
*Division of Plastic Surgery, Department of Surgery, McGill University Health Centre, Montreal, QC, Canada, H3G1A4
1To whom correspondence should be addressed (email anie.philip@mcgill.ca).
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Publisher: Portland Press Ltd
Received:
December 08 2014
Revision Received:
November 23 2015
Accepted:
November 30 2015
Accepted Manuscript online:
November 30 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 Authors; published by Portland Press Limited
2016
Biochem J (2016) 473 (5): 537.
Article history
Received:
December 08 2014
Revision Received:
November 23 2015
Accepted:
November 30 2015
Accepted Manuscript online:
November 30 2015
Citation
Carter Li, Mark A. Hancock, Priyanka Sehgal, Shufeng Zhou, Dieter P. Reinhardt, Anie Philip; Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses. Biochem J 1 March 2016; 473 (5): 537. doi: https://doi.org/10.1042/BJ20141488
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