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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  

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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