Journal article

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.

  • Thejer BM School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Adhikary PP School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Kaur A School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
  • Teakel SL School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Van Oosterum A Life Sciences and Health, Faculty of Science, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Seth I School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Pajic M The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
  • Hannan KM Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
  • Pavy M ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.
  • Poh P ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.
  • Jazayeri JA School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
  • Zaw T Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
  • Pascovici D Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
  • Ludescher M Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.
  • Pawlak M NMI TT Pharmaservices, Protein Profiling, 72770, Reutlingen, Germany.
  • Cassano JC Particles-Biology Interactions Laboratory, Department of Materials Meet Life, Swiss Federal Laboratories for Materials Science & Technology (Empa), Lerchenfeldstrasse 5, CH-9014, St Gallen, Switzerland.
  • Turnbull L The ithree institute, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
  • Jazayeri M Department of Mathematics and Statistics, La Trobe University, Melbourne, VIC, 3086, Australia.
  • James AC Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
  • Coorey CP Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
  • Roberts TL Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
  • Kinder SJ AXT Pty Ltd, Warriewood (Sydney), NSW, 2102, Australia.
  • Hannan RD Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
  • Patrick E School of Mathematics and Statistics, University of Sydney, Sydney, NSW, 2006, Australia.
  • Molloy MP Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
  • New EJ School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
  • Fehm TN Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.
  • Neubauer H Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.
  • Goldys EM ARC Centre of Excellence for Nanoscale BioPhotonics, Macquarie University, Sydney, NSW, 2109, Australia.
  • Weston LA Graham Centre for Agricultural Innovation, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW, 2678, Australia.
  • Cahill MA School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia. mcahill@csu.edu.au.
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  • 2020-04-05
Published in:
  • BMC molecular and cell biology. - 2020
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/154362
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