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

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

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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

Item Type:	Article (Journal)
Additional Information:	6653/31820
Uncontrolled Keywords:	LTBP-2; TGF-β; fibroblast; p38 MAPK; Akt; fibrosis
Subjects:	Q Science > QD Chemistry R Medicine > R Medicine (General) R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Information and Communication Technology Kulliyyah of Information and Communication Technology
Depositing User:	Dr Mohamed Arshad Mohamed Sideek
Date Deposited:	25 Jan 2018 14:52
Last Modified:	13 Mar 2018 13:51
URI:	http://irep.iium.edu.my/id/eprint/31820

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