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

Bashar M. Thejer; Partho P. Adhikary; Amandeep Kaur; Sarah L. Teakel; Ashleigh Van Oosterum; Ishith Seth; Marina Pajic; Katherine M. Hannan; Megan Pavy; Perlita Poh; Jalal A. Jazayeri; Thiri Zaw; Dana Pascovici; Marina Ludescher; Michael Pawlak; Juan C. Cassano; Lynne Turnbull; Mitra Jazayeri; Alexander C. James; Craig P. Coorey; Tara L. Roberts; Simon J. Kinder; Ross D. Hannan; Ellis Patrick; Mark P. Molloy; Elizabeth J. New; Tanja N. Fehm; Hans Neubauer; Ewa M. Goldys; Leslie A. Weston; Michael A. Cahill

doi:10.1186/s12860-020-00256-3

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

Bashar M. Thejer, Partho P. Adhikary, Amandeep Kaur, Sarah L. Teakel, Ashleigh Van Oosterum, Ishith Seth, Marina Pajic, Katherine M. Hannan, Megan Pavy, Perlita Poh, Jalal A. Jazayeri, Thiri Zaw, Dana Pascovici, Marina Ludescher, Michael Pawlak, Juan C. Cassano, Lynne Turnbull, Mitra Jazayeri, Alexander C. James, Craig P. CooreyTara L. Roberts, Simon J. Kinder, Ross D. Hannan, Ellis Patrick, Mark P. Molloy, Elizabeth J. New, Tanja N. Fehm, Hans Neubauer, Ewa M. Goldys, Leslie A. Weston, Michael A. Cahill

Western Sydney University

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	24
Number of pages	24
Journal	BMC Molecular and Cell Biology
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12860-020-00256-3
Publication status	Published - 2020

Open Access - Access Right Statement

Â© 2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Keywords

cancer cells
glycolysis
mitochondria
motility
phosphorylation
proteomics
tumors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12860-020-00256-3

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Thejer, B. M., Adhikary, P. P., Kaur, A., Teakel, S. L., Van Oosterum, A., Seth, I., Pajic, M., Hannan, K. M., Pavy, M., Poh, P., Jazayeri, J. A., Zaw, T., Pascovici, D., Ludescher, M., Pawlak, M., Cassano, J. C., Turnbull, L., Jazayeri, M., James, A. C., ... Cahill, M. A. (2020). PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth. BMC Molecular and Cell Biology, 21(1), Article 24. https://doi.org/10.1186/s12860-020-00256-3

@article{d975d1afe2bd45eca55f1f44eb09d5d1,

title = "PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth",

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.",

keywords = "cancer cells, glycolysis, mitochondria, motility, phosphorylation, proteomics, tumors",

author = "Thejer, {Bashar M.} and Adhikary, {Partho P.} and Amandeep Kaur and Teakel, {Sarah L.} and {Van Oosterum}, Ashleigh and Ishith Seth and Marina Pajic and Hannan, {Katherine M.} and Megan Pavy and Perlita Poh and Jazayeri, {Jalal A.} and Thiri Zaw and Dana Pascovici and Marina Ludescher and Michael Pawlak and Cassano, {Juan C.} and Lynne Turnbull and Mitra Jazayeri and James, {Alexander C.} and Coorey, {Craig P.} and Roberts, {Tara L.} and Kinder, {Simon J.} and Hannan, {Ross D.} and Ellis Patrick and Molloy, {Mark P.} and New, {Elizabeth J.} and Fehm, {Tanja N.} and Hans Neubauer and Goldys, {Ewa M.} and Weston, {Leslie A.} and Cahill, {Michael A.}",

year = "2020",

doi = "10.1186/s12860-020-00256-3",

language = "English",

volume = "21",

journal = "BMC Molecular and Cell Biology",

issn = "2661-8850",

publisher = "BioMed Central",

number = "1",

}

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 2020, 'PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth', BMC Molecular and Cell Biology, vol. 21, no. 1, 24. https://doi.org/10.1186/s12860-020-00256-3

TY - JOUR

T1 - PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

AU - Thejer, Bashar M.

AU - Adhikary, Partho P.

AU - Kaur, Amandeep

AU - Teakel, Sarah L.

AU - Van Oosterum, Ashleigh

AU - Seth, Ishith

AU - Pajic, Marina

AU - Hannan, Katherine M.

AU - Pavy, Megan

AU - Poh, Perlita

AU - Jazayeri, Jalal A.

AU - Zaw, Thiri

AU - Pascovici, Dana

AU - Ludescher, Marina

AU - Pawlak, Michael

AU - Cassano, Juan C.

AU - Turnbull, Lynne

AU - Jazayeri, Mitra

AU - James, Alexander C.

AU - Coorey, Craig P.

AU - Roberts, Tara L.

AU - Kinder, Simon J.

AU - Hannan, Ross D.

AU - Patrick, Ellis

AU - Molloy, Mark P.

AU - New, Elizabeth J.

AU - Fehm, Tanja N.

AU - Neubauer, Hans

AU - Goldys, Ewa M.

AU - Weston, Leslie A.

AU - Cahill, Michael A.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - cancer cells

KW - glycolysis

KW - mitochondria

KW - motility

KW - phosphorylation

KW - proteomics

KW - tumors

UR - https://hdl.handle.net/1959.7/uws:56818

U2 - 10.1186/s12860-020-00256-3

DO - 10.1186/s12860-020-00256-3

M3 - Article

SN - 2661-8850

VL - 21

JO - BMC Molecular and Cell Biology

JF - BMC Molecular and Cell Biology

IS - 1

M1 - 24

ER -

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

Abstract

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Keywords

UN SDGs

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