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PGRMC1 Phosphorylation Affects Cell Shape, Motility, Glycolysis, Mitochondrial Form and Function, and Tumor Growth

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posted on 11.05.2022, 00:50 by BM Thejer, PP Adhikary, A Kaur, SL Teakel, A Van Oosterum, I Seth, M Pajic, KM Hannan, M Pavy, P Poh, JA Jazayeri, T Zaw, D Pascovici, M Ludescher, M Pawlak, JC Cassano, L Turnbull, Mitra JazayeriMitra Jazayeri, AC James, CP Coorey, TL Roberts, SJ Kinder, RD Hannan, E Patrick, MP Molloy, EJ New, TN Fehm, H Neubauer, EM Goldys, LA Weston, MA Cahill
Background: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Results: We demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells. Conclusions: Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

Funding

This work has received no direct Australian competitive grant support since M.A.C.'s relocation to the country in 2008. The present results have been compiled largely due to the generosity of collaborating authors, and by the PhD stipends of B.M.T. and P.P.A. Research was primarily supported by Charles Sturt University internal funds to M.A.C and J.A.J, and by collaborating labs. Open access publication fees were jointly supported by CSU's Faculty of Science, School of Biomedical Sciences, and Research Office. B.M.T. was supported by a PhD scholarship from the Ministry of Higher Education and Research, through the University of Wasit, Iraq. A.K. acknowledges the University of Sydney for a World Scholars Scholarship. E.M.G. acknowledges partial support of Australian Research Council award CE140100003. E.J.N. acknowledges the support of the Australian Research Council (DE120102687) and the Ramaciotti Foundation (ES2012/0051). T.L.R is supported by a Cancer Institute New South Wales Future Research Leader Fellowship. M.P. is supported by a NHMRC RD Wright Biomedical Career Development Fellowship and the Cancer Institute NSW Career Development Fellowship. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

History

Publication Date

01/01/2020

Journal

BMC Molecular and Cell Biology

Volume

21

Issue

1

Article Number

24

Pagination

24p. (p. 1-24)

Publisher

BioMed Central

ISSN

2661-8850

Rights Statement

© The Author(s) 2020. 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.