PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.,BMC Molecular and Cell Biology

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PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.
BMC Molecular and Cell Biology ( IF 2.4 ) Pub Date : 2020-04-03 , DOI: 10.1186/s12860-020-00256-3
Bashar M Thejer _{1,

2} , Partho P Adhikary _{1,

3} , Amandeep Kaur _{4,

5} , Sarah L Teakel ₁ , Ashleigh Van Oosterum ₆ , Ishith Seth ₁ , Marina Pajic _{7,

8} , Katherine M Hannan _{9,

10} , Megan Pavy ₁₀ , Perlita Poh ₁₀ , Jalal A Jazayeri ₁ , Thiri Zaw ₁₁ , Dana Pascovici ₁₁ , Marina Ludescher ₁₂ , Michael Pawlak ₁₃ , Juan C Cassano ₁₄ , Lynne Turnbull _{15,

16} , Mitra Jazayeri ₁₇ , Alexander C James _{18,

19,

20} , Craig P Coorey _{18,

21} , Tara L Roberts _{18,

19,

20,

21} , Simon J Kinder ₂₂ , Ross D Hannan _{9,

10,

23,

24,

25} , Ellis Patrick ₂₆ , Mark P Molloy _{11,

27} , Elizabeth J New ₄ , Tanja N Fehm ₁₂ , Hans Neubauer ₁₂ , Ewa M Goldys _{28,

29} , Leslie A Weston _{30,

31} , Michael A Cahill _{1,

10}

Affiliation

School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
Department of Biology, College of Science, University of Wasit, Wasit, 00964, Iraq.
Present address: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, V6T 1Z4, Canada.
School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia.
Present address: School of Medical Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
Life Sciences and Health, Faculty of Science, Charles Sturt University, Wagga Wagga, NSW, 2650, Australia.
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.
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.
Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, 2109, Australia.
Department of Gynecology and Obstetrics, University Women's Hospital of Dusseldorf, 40225, Dusseldorf, Germany.
NMI TT Pharmaservices, Protein Profiling, 72770, Reutlingen, Germany.
Particles-Biology Interactions Laboratory, Department of Materials Meet Life, Swiss Federal Laboratories for Materials Science & Technology (Empa), Lerchenfeldstrasse 5, CH-9014, St Gallen, Switzerland.
The ithree institute, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Present address: GE Healthcare Life Sciences, Issaquah, WA, 98027, USA.
Department of Mathematics and Statistics, La Trobe University, Melbourne, VIC, 3086, Australia.
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.
AXT Pty Ltd, Warriewood (Sydney), NSW, 2102, 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.
School of Mathematics and Statistics, University of Sydney, Sydney, NSW, 2006, Australia.
Present address: The Kolling Institute, The University of Sydney, St Leonards (Sydney), NSW, 2064, Australia.
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.
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.

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.

中文翻译：

PGRMC1 磷酸化影响细胞形状、运动性、糖酵解、线粒体形式和功能以及肿瘤生长。

背景黄体酮受体膜成分 1 (PGRMC1) 在许多癌细胞中表达，与有害的患者预后相关。它含有磷酸化酪氨酸，其进化先于后口动物原肠胚形成和组织分化机制。结果我们证明，操纵 MIA PaCa-2 (MP) 细胞中的 PGRMC1 磷酸化状态可产生广泛的多效性效应。相对于过表达血凝素标记的野生型 (WT) PGRMC1-HA 的亲本细胞，表达 PGRMC1-HA-S57A/S181A 双突变体 (DM) 的细胞表现出参与能量代谢和线粒体功能的蛋白质水平降低，并且改变葡萄糖代谢表明瓦尔堡效应的调节。这与 PI3K/AKT 活性增加、细胞形状、肌动蛋白细胞骨架、运动性和线粒体特性改变有关。 S57A/Y180F/S181A 三重突变体 (TM) 表明 Y180 参与 PI3K/AKT 激活。 Y180F 突变强烈减弱 NOD-SCID γ 小鼠皮下异种移植肿瘤的生长。在其他地方，我们证明了这些细胞的代谢、突变发生率和表观遗传状态发生了改变。结论总而言之，这些结果表明 PGRMC1 磷酸化状态的突变操作可发挥与癌症和其他细胞生物学相关的广泛多效性效应。

更新日期：2020-04-22

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