Bao, Leyuan, Fearnley, Gareth W., Lin, Chi-Chuan, Odell, Adam ORCID: https://orcid.org/0000-0002-6855-7214, Redondo, Ana C., Kinsella, Gemma K., Findlay, John B. C., Ladbury, John E. ORCID: https://orcid.org/0000-0002-6328-7200, Harrison, Michael A. and Ponnambalam, Sreenivasan ORCID: https://orcid.org/0000-0002-4452-7619 (2021) Calcium-binding protein S100A6 interaction with VEGF receptor integrates signaling and trafficking pathways. BioRxiv. (Unpublished)

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Abstract

The mammalian endothelium which lines all blood vessels responds to soluble factors which control vascular development and sprouting. Endothelial cells bind to vascular endothelial growth factor A via two different receptor tyrosine kinases (VEGFR1, VEGFR2) which regulate such cellular responses. The integration of VEGFR signal transduction and membrane trafficking is not well understood. Here, we used a yeast-based membrane protein screen to identify VEGFR-interacting factor(s) which modulate endothelial cell function. By screening a human endothelial cDNA library, we identified a calcium-binding protein, S100A6, which can interact with either VEGFR. We found that S100A6 binds in a calcium-dependent manner to either VEGFR1 or VEGFR2. S100A6 binding was mapped to the VEGFR2 tyrosine kinase domain. Depletion of S100A6 impacts on VEGF-A-regulated signaling through the canonical mitogen-activated protein kinase (MAPK) pathway. Furthermore, S100A6 depletion caused contrasting effects on biosynthetic VEGFR delivery to the plasma membrane. Co-distribution of S100A6 and VEGFRs on tubular profiles suggest the presence of transport carriers that facilitate VEGFR trafficking. We propose a mechanism whereby S100A6 acts as a calcium-regulated switch which facilitates biosynthetic VEGFR trafficking from the TGN-to-plasma membrane. VEGFR-S100A6 interactions thus enable integration of signaling and trafficking pathways in controlling the endothelial response to VEGF-A.

Item Type:	Article
Additional Information:	Preprint
Status:	Unpublished
DOI:	10.1101/2021.07.29.454311
School/Department:	School of Science, Technology and Health
URI:	https://ray.yorksj.ac.uk/id/eprint/5556

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