The evolutionary appearance of signaling motifs in PGRMC1

Cahill, Michael A.

doi:10.5582/bst.2017.01009

Cited by 34 publications

(43 citation statements)

References 53 publications

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“…It will be interesting to examine whether that treatment mimics the effects of phosphorylation. (PGRMC2 possesses cognates to PGRMC1 Y180 and S181, as well as heme-chelating Y113 (Cahill, 2017). )…”

Section: Discussionmentioning

confidence: 99%

“…We stably transfected MP cells with the hemagglutinin (HA) epitope-tagged PGRMC1-HA plasmids including the wild-type (WT) sequence (Suchanek et al, 2005), the S57A/S181A DM (Neubauer et al, 2008), or a novel S57A/Y180F/S181A triple mutant (TM), which removed the phosphate acceptor of Y180 (Cahill, 2007(Cahill, , 2017 2016b) ( Figure 1A). Three independent stable cell lines from each group expressed both 32 kDa 3xHA-tagged exogenous and a 24 kDa endogenous PGRMC1 species, whereas only the 24 kDa species was present in MP cells ( Figure 1B-D).…”

Section: Pgrmc1 Phosphorylation Status Alters Cellular Morphologymentioning

confidence: 99%

“…We hypothesized that PGRMC1 is a signal hub protein with wide ranging effects on cancer and general cell biology (Cahill, 2017;Cahill et al, 2016a;Cahill et al, 2016b;Cahill and Medlock, 2017). The highly conserved motif at Y180/S181 arose early in animal evolution concurrently with the embryological organizer of gastrulation (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Spemann-Mangold organizer), and prior to the evolution of deuterostomes (Cahill, 2017;Hehenberger et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Thejer

Adhikary

Kaur

et al. 2019

Preprint

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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. Here, 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 mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.

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Section: Discussionmentioning

confidence: 99%

Section: Pgrmc1 Phosphorylation Status Alters Cellular Morphologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Spemann-Mangold organizer), and prior to the evolution of deuterostomes (Cahill, 2017;Hehenberger et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Thejer

Adhikary

Kaur

et al. 2019

Preprint

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“…In triple A syndrome, altered CYP P450 enzyme activity would consecutively contribute to adrenal atrophy (Jühlen et al, 2016). Human PGRMC1 and PGRMC2 share 67 % of their protein sequence (Cahill, 2017;Cahill and Medlock, 2017). Deficiency of either PGRMC1 or PGRMC2 decreases the anti-apoptotic and anti-mitotic action of progesterone .…”

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confidence: 99%

Triple A patient cells suffering from mitotic defects fail to localize PGRMC1 to mitotic kinetochore fibers

Jühlen

Landgraf

Hübner

et al. 2018

Preprint

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Abbreviations: ALADIN, alacrima-achalasia-adrenal insufficiency neurologic disorder; CYP, cytochrome P450; ER, endoplasmic reticulum; GFP, green fluorescent protein; NADPH, Nicotinamide adenine dinucleotide phosphate; NUP, nucleoporin; PGRMC1 and 2, progesterone receptor membrane component 1 and 2 Investigating cell division in human adrenal cells we show that proliferation is decreased upon overexpression of ALADIN, PGRMC1 or PGRMC2.• In immunofluorescence experiments using human adrenal cells and triple A patient fibroblasts we observed that during cell division PGRMC1 localizes to the microtubule kinetochore-fibers in metaphase and to the mid-body in telophase.• Depletion of ALADIN results in mis-localization of Aurora A and PGRMC1 in metaphase cells of the human adrenal cell line and fibroblasts derived from patients with triple A syndrome.• In real time PCR using RNA of fibroblasts of triple A syndrome patients and healthy controls we measured an increased expression of PGRMC2 in cells with ALADIN mis-function compared to the control cells.• We hypothesize that a loss of the regulatory interaction between ALADIN and PGRMC2 leads to an over-regulation and over-expression of PGRMC2 and displaces PGRMC1 at the metaphase spindle.This diminishing of PGRMC1 concentration at kinetochore fibers may lead to mitotic errors and proliferation arrest. ABSTRACTMembrane-associated progesterone receptors are restricted to the endoplasmic reticulum and are shown to regulate the activity of cytochrome P450 enzymes which are involved in steroidogenesis or drug detoxification. PGRMC1 and PGRMC2 belong to this group of microsomal receptors and are of interest due to their suspected role during cell cycle. PGRMC1 and PGRMC2 are thought to bind to each other thereby suppressing entry into mitosis. We could previously report that PGRMC2 interacts with the nucleoporin ALADIN which when mutated results in the autosomal recessive disorder triple A syndrome. ALADIN is a novel regulator of mitotic controller Aurora kinase A and depletion of this nucleoporin leads to microtubule instability. In the current study, we present that proliferation is decreased when ALADIN, PGRMC1 or PGRMC2 are over-expressed. Furthermore, we find that depletion of ALADIN results in mis-localization of Aurora kinase A and PGRMC1 in metaphase cells. Additionally, PGRMC2 is over-expressed in triple A patient fibroblasts. Our results emphasize the possibility that loss of the regulatory interaction between ALADIN and PGRMC2 gives rise to a depletion of PGRMC1 at kinetochore fibers and to mitotic errors. This observation may explain part of the symptoms seen in triple A syndrome patients.Cells were seeded in 24-well culture dishes at a density of 0.4 x10 5 cells/well 24 h before proliferation analysis. Confluence measurement was done using live cell imaging on IncuCyte Zoom (Essen BioScience, Ann Arbor MI, USA) over at least 65 h. Measurement was done at least in triplicate and experiments were repeated at least twice. Immunofluorescence microscopyCells grown on g...

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Re-evaluation of protein kinase CK2 pleiotropy: new insights provided by a phosphoproteomics analysis of CK2 knockout cells

Franchin

Borgo

Cesaro

et al. 2017

Cell. Mol. Life Sci.

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CK2 denotes a ubiquitous and pleiotropic protein kinase whose holoenzyme is composed of two catalytic (α and/or α') and two regulatory β subunits. The CK2 consensus sequence, S/T-x-x-D/E/pS/pT is present in numerous phosphosites, but it is not clear how many of these are really generated by CK2. To gain information about this issue, advantage has been taken of C2C12 cells entirely deprived of both CK2 catalytic subunits by the CRISPR/Cas9 methodology. A comparative SILAC phosphoproteomics analysis reveals that, although about 30% of the quantified phosphosites do conform to the CK2 consensus, only one-third of these are substantially reduced in the CK2α/α' cells, consistent with their generation by CK2. A parallel study with C2C12 cells deprived of the regulatory β subunit discloses a role of this subunit in determining CK2 targeting. We also find that phosphosites notoriously generated by CK2 are not fully abrogated in CK2α/α' cells, while some phosphosites unrelated to CK2 are significantly altered. Collectively taken our data allow to conclude that the phosphoproteome generated by CK2 is not as ample and rigidly pre-determined as it was believed before. They also show that the lack of CK2 promotes phosphoproteomics perturbations attributable to kinases other than CK2.

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The evolutionary appearance of signaling motifs in PGRMC1

Cited by 34 publications

References 53 publications

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Triple A patient cells suffering from mitotic defects fail to localize PGRMC1 to mitotic kinetochore fibers

Re-evaluation of protein kinase CK2 pleiotropy: new insights provided by a phosphoproteomics analysis of CK2 knockout cells

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