Protrudin regulates FAK activation, endothelial cell migration and angiogenesis

Arora, Amita, Kivelä, Annukka M., Wang, Ling, Minkeviciene, Rimante, Taskinen, Juuso H., Zhang, Birong, Koponen, Annika, Sun, Jing, Shirane, Michiko, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Hotulainen, Pirta, Raiborg, Camilla and Olkkonen, Vesa M. 2022. Protrudin regulates FAK activation, endothelial cell migration and angiogenesis. Cellular and Molecular Life Sciences 79 (4) , 220. 10.1007/s00018-022-04251-z

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Abstract

During angiogenesis, endothelial cells form protrusive sprouts and migrate towards the angiogenic stimulus. In this study, we investigate the role of the endoplasmic reticulum (ER)-anchored protein, Protrudin, in endothelial cell protrusion, migration and angiogenesis. Our results demonstrate that Protrudin regulates angiogenic tube formation in primary endothelial cells, Human umbilical vein endothelial cells (HUVECs). Analysis of RNA sequencing data and its experimental validation revealed cell migration as a prominent cellular function affected in HUVECs subjected to Protrudin knockdown. Further, our results demonstrate that knockdown of Protrudin inhibits focal adhesion kinase (FAK) activation in HUVECs and human aortic endothelial cells (HAECs). This is associated with a loss of polarized phospho-FAK distribution upon Protrudin knockdown as compared to Protrudin expressing HUVECs. Reduction of Protrudin also results in a perinuclear accumulation of mTOR and a decrease in VEGF-mediated S6K activation. However, further experiments suggest that the observed inhibition of angiogenesis in Protrudin knockdown cells is not affected by mTOR disturbance. Therefore, our findings suggest that defects in FAK activation and its abnormal subcellular distribution upon Protrudin knockdown are associated with a detrimental effect on endothelial cell migration and angiogenesis. Furthermore, mice with global Protrudin deletion demonstrate reduced retinal vascular progression. To conclude, our results provide evidence for a novel key role of Protrudin in endothelial cell migration and angiogenesis.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Springer
ISSN:	1420-682X
Date of First Compliant Deposit:	26 May 2022
Date of Acceptance:	15 March 2022
Last Modified:	09 May 2023 11:02
URI:	https://orca.cardiff.ac.uk/id/eprint/150060

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