Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress

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Hewawasam, NV, Lhaf, F, Taylor, HA, Viloria, K, Austin, A, King, A, Jones, P, Jones, L, Turner, MD ORCID: https://orcid.org/0000-0001-7175-1053 and Hill, NJ, 2020. Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress. Scientific Reports, 10 (1): 15741.

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Official URL: https://doi.org/10.1038/s41598-020-72939-y

Abstract

Regenerative medicine approaches to enhancing beta cell growth and survival represent potential treatments for diabetes. It is known that growth factors such as insulin, IGF-1 and HGF support beta cell growth and survival, but in people with type 2 diabetes the destructive effects of metabolic stress predominate and beta cell death or dysfunction occurs. In this study we explore the novel hypothesis that regulation of growth factor receptor trafficking can be used to promote islet beta cell survival. Growth factor signalling is dependent on the presence of cell surface receptors. Endosomal trafficking and subsequent recycling or degradation of these receptors is controlled by the Rab GTPase family of proteins. We show that Rab7a siRNA inhibition enhances IGF-1 and HGF signalling in beta cells and increases expression of the growth factor receptors IGF-1R and c-Met. Furthermore, Rab7a inhibition promotes beta cell growth and islet survival, and protects against activation of apoptosis and autophagy pathways under conditions of metabolic stress. This study therefore demonstrates that Rab7a-mediated trafficking of growth factor receptors controls beta cell survival. Pharmaceutical Rab7a inhibition may provide a means to promote beta cell survival in the context of metabolic stress and prevent the onset of type 2 diabetes.

Item Type:	Journal article
Publication Title:	Scientific Reports
Creators:	Hewawasam, N.V., Lhaf, F., Taylor, H.A., Viloria, K., Austin, A., King, A., Jones, P., Jones, L., Turner, M.D. and Hill, N.J.
Publisher:	Springer Science and Business Media LLC
Date:	December 2020
Volume:	10
Number:	1
Identifiers:	Number Type 10.1038/s41598-020-72939-y DOI 1369797 Other
Rights:	© The Author(s) 2020. Open Access 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	20 Oct 2020 13:06
Last Modified:	31 May 2021 15:15
URI:	https://irep.ntu.ac.uk/id/eprint/41367