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

Thejer, BM; Adhikary, PP; Kaur, A; Teakel, SL; Van Oosterum, A; Seth, I; Pajic, M; Hannan, KM; Pavy, M; Poh, P; Jazayeri, JA; Zaw, T; Pascovici, D; Ludescher, M; Pawlak, M; Cassano, JC; Turnbull, L; Jazayeri, M; James, AC; Coorey, CP; Roberts, TL; Kinder, SJ; Hannan, RD; Patrick, E; Molloy, MP; New, EJ; Fehm, TN; Neubauer, H; Goldys, EM; Weston, LA; Cahill, MA

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

Thejer, BM Adhikary, PP Kaur, A Teakel, SL Van Oosterum, A Seth, I Pajic, M Hannan, KM Pavy, M Poh, P Jazayeri, JA Zaw, T Pascovici, D Ludescher, M Pawlak, M Cassano, JC Turnbull, L

Jazayeri, M James, AC Coorey, CP Roberts, TL Kinder, SJ Hannan, RD Patrick, E Molloy, MP New, EJ Fehm, TN Neubauer, H Goldys, EM Weston, LA Cahill, MA

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Publisher:: BMC
Publication Type:: Journal Article
Citation:: BMC molecular and cell biology, 2020, 21, (1), pp. 24
Issue Date:: 2020-04-03

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Field	Value	Language
dc.contributor.author	Thejer, BM
dc.contributor.author	Adhikary, PP
dc.contributor.author	Kaur, A
dc.contributor.author	Teakel, SL
dc.contributor.author	Van Oosterum, A
dc.contributor.author	Seth, I
dc.contributor.author	Pajic, M
dc.contributor.author	Hannan, KM
dc.contributor.author	Pavy, M
dc.contributor.author	Poh, P
dc.contributor.author	Jazayeri, JA
dc.contributor.author	Zaw, T
dc.contributor.author	Pascovici, D
dc.contributor.author	Ludescher, M
dc.contributor.author	Pawlak, M
dc.contributor.author	Cassano, JC
dc.contributor.author	Turnbull, L https://orcid.org/0000-0002-9255-9033
dc.contributor.author	Jazayeri, M
dc.contributor.author	James, AC
dc.contributor.author	Coorey, CP
dc.contributor.author	Roberts, TL
dc.contributor.author	Kinder, SJ
dc.contributor.author	Hannan, RD
dc.contributor.author	Patrick, E
dc.contributor.author	Molloy, MP
dc.contributor.author	New, EJ
dc.contributor.author	Fehm, TN
dc.contributor.author	Neubauer, H
dc.contributor.author	Goldys, EM
dc.contributor.author	Weston, LA
dc.contributor.author	Cahill, MA
dc.date.accessioned	2021-05-21T04:48:24Z
dc.date.available	2020-03-04
dc.date.available	2021-05-21T04:48:24Z
dc.date.issued	2020-04-03
dc.identifier.citation	BMC molecular and cell biology, 2020, 21, (1), pp. 24
dc.identifier.issn	2661-8850
dc.identifier.issn	2661-8850
dc.identifier.uri	http://hdl.handle.net/10453/149045
dc.description.abstract	<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.
dc.format	Electronic
dc.language	eng
dc.publisher	BMC
dc.relation	http://purl.org/au-research/grants/arc/CE140100003
dc.relation.ispartof	BMC molecular and cell biology
dc.relation.isbasedon	10.1186/s12860-020-00256-3
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, SCID
dc.subject.mesh	Neoplasms
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Receptors, Progesterone
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Movement
dc.subject.mesh	Cell Shape
dc.subject.mesh	Energy Metabolism
dc.subject.mesh	Glycolysis
dc.subject.mesh	Phosphorylation
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Movement
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Shape
dc.subject.mesh	Energy Metabolism
dc.subject.mesh	Glycolysis
dc.subject.mesh	Humans
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Mice, SCID
dc.subject.mesh	Mitochondria
dc.subject.mesh	Neoplasms
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Phosphorylation
dc.subject.mesh	Receptors, Progesterone
dc.title	PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	England
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	open_access	*
dc.date.updated	2021-05-21T04:48:22Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	1

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/149045