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A Bone Morphogenetic Protein (BMP)-derived peptide based on the Type I receptor-binding site modifies cell-type dependent BMP signalling

Title: A Bone Morphogenetic Protein (BMP)-derived peptide based on the Type I receptor-binding site modifies cell-type dependent BMP signalling
Authors: Tong, Z
Guo, J
Glen, RC
Morrell, NW
Li, W
Item Type: Journal Article
Abstract: Bone morphogenetic proteins (BMPs) are multifunctional cytokines of the transforming growth factor β (TGFβ) superfamily with potential therapeutic applications due to their broad biological functionality. Designing BMP mimetics with specific activity will contribute to the translational potential of BMP-based therapies. Here, we report a BMP9 peptide mimetic, P3, designed from the type I receptor binding site, which showed millimolar binding affinities for the type I receptor activin receptor like kinase 1 (ALK1), ALK2 and ALK3. Although showing no baseline activity, P3 significantly enhanced BMP9-induced Smad1/5 phosphorylation as well as ID1, BMPR2, HEY1 and HEY2 gene expression in pulmonary artery endothelial cells (hPAECs), and this activity is dependent on its alpha helix propensity. However, in human dermal microvascular endothelial cells, P3 did not affect BMP9-induced Smad1/5 phosphorylation, but potently inhibited ALK3-dependent BMP4-induced Smad1/5 phosphorylation and gene expression. In C2C12 mouse myoblast cells, P3 had no effect on BMP9-induced osteogenic signalling, which is primarily mediated by ALK2. Interestingly, a previously published peptide from the knuckle region of BMP9 was found to inhibit BMP4-induced Smad1/5 phosphorylation. Together, our data identify a BMP9-derived peptide that can selectively enhance ALK1-mediated BMP9 signalling in hPAECs and modulate BMP9 and BMP4 signalling in a cell type-specific manner.
Issue Date: 17-Sep-2019
Date of Acceptance: 29-Aug-2019
URI: http://hdl.handle.net/10044/1/75049
DOI: 10.1038/s41598-019-49758-x
ISSN: 2045-2322
Publisher: Nature Publishing Group
Start Page: 1
End Page: 9
Journal / Book Title: Scientific Reports
Volume: 9
Copyright Statement: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
KINASE 3
DIFFERENTIATION
ACTIVATION
MECHANISM
AGONIST
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
KINASE 3
DIFFERENTIATION
ACTIVATION
MECHANISM
AGONIST
0601 Biochemistry and Cell Biology
0299 Other Physical Sciences
Publication Status: Published
Article Number: ARTN 13446
Online Publication Date: 2019-09-17
Appears in Collections:Department of Metabolism, Digestion and Reproduction