A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways

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, altho...

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Main Authors:	Sideek, Mohamed Arshad, Smith, Joshua J., Menz, Clementine, Adams, Julian R. J., Cowin, Allison J., Gibson, Mark A.
Format:	Article
Language:	English English
Published:	Multidisciplinary Digital Publishing Institute (MDPI) 2017
Subjects:	QD Chemistry R Medicine (General) RA0421 Public health. Hygiene. Preventive Medicine
Online Access:	http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/1/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates.pdf http://irep.iium.edu.my/31820/2/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates_scopus.pdf

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spelling	iium-318202018-03-13T05:51:25Z http://irep.iium.edu.my/31820/ A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways Sideek, Mohamed Arshad Smith, Joshua J. Menz, Clementine Adams, Julian R. J. Cowin, Allison J. Gibson, Mark A. QD Chemistry R Medicine (General) RA0421 Public health. Hygiene. Preventive Medicine 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 Multidisciplinary Digital Publishing Institute (MDPI) 2017-10-09 Article PeerReviewed application/pdf en http://irep.iium.edu.my/31820/1/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates.pdf application/pdf en http://irep.iium.edu.my/31820/2/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates_scopus.pdf Sideek, Mohamed Arshad and Smith, Joshua J. and Menz, Clementine and Adams, Julian R. J. and Cowin, Allison J. and Gibson, Mark A. (2017) A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways. International Journal of Molecular Sciences, 18 (10). pp. 1-17. ISSN 1661-6596 E-ISSN 1422-0067 http://www.mdpi.com/1422-0067/18/10/2114 10.3390/ijms18102114
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English English
topic	QD Chemistry R Medicine (General) RA0421 Public health. Hygiene. Preventive Medicine
spellingShingle	QD Chemistry R Medicine (General) RA0421 Public health. Hygiene. Preventive Medicine Sideek, Mohamed Arshad Smith, Joshua J. Menz, Clementine Adams, Julian R. J. Cowin, Allison J. Gibson, Mark A. A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
description	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
format	Article
author	Sideek, Mohamed Arshad Smith, Joshua J. Menz, Clementine Adams, Julian R. J. Cowin, Allison J. Gibson, Mark A.
author_facet	Sideek, Mohamed Arshad Smith, Joshua J. Menz, Clementine Adams, Julian R. J. Cowin, Allison J. Gibson, Mark A.
author_sort	Sideek, Mohamed Arshad
title	A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
title_short	A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
title_full	A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
title_fullStr	A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
title_full_unstemmed	A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways
title_sort	central bioactive region of ltbp-2 stimulates the expression of tgf-β1 in fibroblasts via akt and p38 signalling pathways
publisher	Multidisciplinary Digital Publishing Institute (MDPI)
publishDate	2017
url	http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/ http://irep.iium.edu.my/31820/1/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates.pdf http://irep.iium.edu.my/31820/2/31820_A%20Central%20Bioactive%20Region%20of%20LTBP-2%20Stimulates_scopus.pdf
first_indexed	2023-09-18T20:45:58Z
last_indexed	2023-09-18T20:45:58Z
_version_	1777409676722307072

A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways

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