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https://hdl.handle.net/2440/110142
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Type: | Journal article |
Title: | A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via Akt and p38 signalling pathways |
Other Titles: | A central bioactive region of LTBP-2 stimulates the expression of TGF-beta1 in fibroblasts via Akt and p38 signalling pathways |
Author: | Sideek, M. Smith, J. Menz, C. Adams, J. Cowin, A. Gibson, M. |
Citation: | International Journal of Molecular Sciences, 2017; 18(10):1-17 |
Publisher: | MDPI |
Issue Date: | 2017 |
ISSN: | 1422-0067 1422-0067 |
Statement of Responsibility: | Mohamed A. Sideek , Joshua Smith, Clementine Menz, Julian R. J. Adams, Allison J. Cowin and Mark A. Gibson |
Abstract: | Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-β1 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-β1 levels in the medium. However, the TGF-β1 increase was due to an upregulation of TGF-β1 expression and secretion rather than a displacement of matrix-stored TGF-β1. The secreted TGF-β1 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-β expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-β1 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins β1 and αVβ5 showed no reduction of LTBP-2 stimulation of TGF-β1. However, TGF-β1 upregulation was partially inhibited by anti-αVβ3 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-β1 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-β1 signalling. |
Keywords: | Akt LTBP-2 TGF-β fibroblast fibrosis p38 MAPK |
Rights: | © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
DOI: | 10.3390/ijms18102114 |
Published version: | http://dx.doi.org/10.3390/ijms18102114 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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hdl_110142.pdf | Published Version | 1.58 MB | Adobe PDF | View/Open |
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