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

Animals Cell Line, Tumor Cell Movement Cell Proliferation Cell Shape Energy Metabolism Glycolysis Humans Membrane Proteins / biosynthesis Mice Mice, Inbred NOD Mice, SCID Mitochondria / metabolism Neoplasms Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Receptors, Progesterone / biosynthesis
Cytochrome P450 Invasion Mesenchymal amoeboid transition Metabolism Migration Mitochondria Proteomics Tumor biology

Journal

BMC molecular and cell biology
ISSN: 2661-8850
Titre abrégé: BMC Mol Cell Biol
Pays: England
ID NLM: 101741148

Informations de publication

Date de publication:
03 Apr 2020
Historique:
received: 16 01 2020
accepted: 04 03 2020
entrez: 5 4 2020
pubmed: 5 4 2020
medline: 30 12 2020
Statut: epublish

Résumé

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. 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. Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

Sections du résumé

BACKGROUND 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 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 CONCLUSIONS
Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

Identifiants

DOI: 10.1186/s12860-020-00256-3 PMID: 32245408 PMC: PMC7119165
pubmed: 32245408
doi: 10.1186/s12860-020-00256-3
pii: 10.1186/s12860-020-00256-3
pmc: PMC7119165
doi:

Substances chimiques

Membrane Proteins 0
PGRMC1 protein, human 0
PGRMC1 protein, mouse 0
Receptors, Progesterone 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

24

Subventions

Organisme : Iraqi Cultural Attaché in Canberra (AUS)
ID : N/A
Organisme : Charles Sturt University
ID : N/A
Organisme : University of Sydney
ID : World Scholars Scholarship
Organisme : Australian Research Council
ID : CE140100003
Organisme : Australian Research Council (AU)
ID : DE120102687
Organisme : Ramaciotti Foundations
ID : ES2012/0051
Organisme : Cancer Institute NSW (AU)
ID : Future Research Leader Fellowship
Organisme : National Health and Medical Research Council
ID : RD Wright Biomedical Career Development Fellowship
Organisme : Cancer Institute NSW
ID : Career Development Fellowship

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Auteurs

Bashar M Thejer (BM)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
Department of Biology, College of Science, University of Wasit, Wasit, 00964, Iraq.

Partho P Adhikary (PP)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
Present address: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, V6T 1Z4, Canada.

Amandeep Kaur (A)

School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
Present address: School of Medical Sciences, University of Sydney, Sydney, NSW, 2006, Australia.

Sarah L Teakel (SL)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.

Ashleigh Van Oosterum (A)

Life Sciences and Health, Faculty of Science, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.

Ishith Seth (I)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.

Marina Pajic (M)

The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, 2010, NSW, Australia.

Katherine M Hannan (KM)

Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.

Megan Pavy (M)

ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.

Perlita Poh (P)

ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.

Jalal A Jazayeri (JA)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.

Thiri Zaw (T)

Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.

Dana Pascovici (D)

Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.

Marina Ludescher (M)

Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.

Michael Pawlak (M)

NMI TT Pharmaservices, Protein Profiling, 72770, Reutlingen, Germany.

Juan C 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.

Lynne Turnbull (L)

The ithree institute, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Present address: GE Healthcare Life Sciences, Issaquah, WA, 98027, USA.

Mitra Jazayeri (M)

Department of Mathematics and Statistics, La Trobe University, Melbourne, VIC, 3086, Australia.

Alexander C James (AC)

Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia.
South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, NSW, 2170, Australia.

Craig P Coorey (CP)

Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
School of Medicine and University of Queensland Centre for Clinical Research, Herston, QLD, 4006, Australia.

Tara L Roberts (TL)

Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia.
School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia.
South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, NSW, 2170, Australia.
School of Medicine and University of Queensland Centre for Clinical Research, Herston, QLD, 4006, Australia.

Simon J Kinder (SJ)

AXT Pty Ltd, Warriewood (Sydney), NSW, 2102, Australia.

Ross D Hannan (RD)

Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia.
Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3168, Australia.

Ellis Patrick (E)

School of Mathematics and Statistics, University of Sydney, Sydney, NSW, 2006, Australia.

Mark P Molloy (MP)

Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
Present address: The Kolling Institute, The University of Sydney, St Leonards (Sydney), NSW, 2064, Australia.

Elizabeth J New (EJ)

School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.

Tanja N Fehm (TN)

Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.

Hans Neubauer (H)

Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.

Ewa M Goldys (EM)

ARC Centre of Excellence for Nanoscale BioPhotonics, Macquarie University, Sydney, NSW, 2109, Australia.
Present address: The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, 2052, Australia.

Leslie A Weston (LA)

Graham Centre for Agricultural Innovation, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW, 2678, Australia.
School of Agricultural and Wine Sciences, Charles Sturt University, Boorooma Street, Wagga Wagga, NSW, 2678, Australia.

Michael A Cahill (MA)

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia. mcahill@csu.edu.au.
ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Canberra, 2601, Australia. mcahill@csu.edu.au.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Phénomènes physiologiques › Mouvement cellulaire › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Forme de la cellule › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Glycolyse › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Tumeurs › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Métabolisme › Phosphorylation › PGRMC1 phosphorylation affects cell shape,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs à la progestérone › PGRMC1 phosphorylation affects cell shape,...