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

Bashar M. Thejer, Partho P. Adhikary, Amandeep Kaur, Sarah L. Teakel, Ashleigh Van Oosterum, Ishith Seth, Marina Pajic, Katherine M. Hannan, Megan Pavy, Perlita Poh, Jalal A. Jazayeri, Thiri Zaw, Dana Pascovici, Marina Ludescher, Michael Pawlak, Juan C. Cassano, Lynne Turnbull, Mitra Jazayeri, Alexander C. James, Craig P. CooreyTara L. Roberts, Simon J. Kinder, Ross D. Hannan, Ellis Patrick, Mark P. Molloy, Elizabeth J. New, Tanja N. Fehm, Hans Neubauer, Ewa M. Goldys, Leslie A. Weston, Michael A. Cahill

Research output: Contribution to journalArticlepeer-review

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Abstract

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.

Original languageEnglish
Article number24
Pages (from-to)1-24
Number of pages24
JournalBMC Molecular and Cell Biology
Volume21
DOIs
Publication statusPublished - 3 Apr 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Cytochrome P450
  • Invasion
  • Mesenchymal amoeboid transition
  • Metabolism
  • Migration
  • Mitochondria
  • Proteomics
  • Tumor biology

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