Thejer, Bashar M.Adhikary, Partho P.Kaur, AmandeepTeakel, Sarah L.van Oosterum, AshleighSeth, IshithPajic, MarinaHannan, KatePavy, MeganPoh, PerlitaJazayeri, Jalal A.Zaw, ThiriPascovici, DanaLudescher, MarinaHannan, RossCAHILL, Michael2023-02-212023-02-212661-8850http://hdl.handle.net/1885/285817Background 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.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.application/pdfen-AU© 2020 The authorshttp://creativecommons.org/licenses/by/4.0/MitochondriaMigrationInvasionMetabolismCytochrome P450Mesenchymal amoeboid transitionProteomicsTumor biology202010.1186/s12860-020-00256-32023-10-22Creative Commons Attribution licence