What is it about?
We show that mutation of the regulatory phosphorylation sites surrounding PGRMC1 tyrosine 180 cause dramatic changes in cells: the mutations go off like bombshells, dramatically affecting cell metabolism, mitochondrial form and function, cell shape, migratory ability, and tumour-forming ability.
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Why is it important?
We show that perturbations of the PGRMC1 tyrosine 180 (Y180) motif exert really dramatic effects on cells. We had previously shown that removing two negative regulatory sites surrounding the tyrosine 180 motif enabled cells to surive otherwise lethal conditions [1]. Here we newly show that Y180 is critical to the motif, being e.g. absolutely required for these cells to efficiently form tumours in mice. In a companion paper [2] we show that these effects dramatically change the epigenetic methylation status of the genome. This invoves the DNA bases being labelled iwth a methyl group (essentially a single carbon tag), which the cell's systems recognise to silence or activate gene expression. In another paper [3] we show that Y180 appeared in evolution at the same time as the gastrulation organiser, which initiates the csacade of events that lead to embryological tisssue differentation during animal development. It looks like PGRMC1 is right at the fulcrum of a signal network that regulates cell differentiation status, and so should be crucially important for disease.
Perspectives
This paper stands in tribute and acknowledgement of all of my colleagues from ProteoSys in Mainz, Germany. We had filed a patent application for the use of PGRMC1 phosphorylation as a diagnostic in cancer already by 2005 (WO2006029836). At the time we were that far ahead of the field. As it was, ProteoSys management chose not to pursue PGRMC1 to concentrate its limited start-up funds in support of another project in Alzheimer's disease. Ironically, PGRMC1 turns out to be a key molecule in the mechanism of action of a compound that induces synaptorestoration Alzheimer's disease [4], leading to improved cognition in animal models, and currently in Phase 2 clinical trial [5]. It now looks like like PGRMC1 phosphorylation (which we discovered at ProteoSys [2]) is one of the pivotal features upon which animal evolution, embryology, and healthy differentiation are based [2,3]. PGRMC1 is an animal fulcrum molecule. Sadly, because I chose to live in a regional setting when I relocated back to Australia in 2008 (as I had successfully done in Germany for 12 years previously) the Australian national competitive grant system was unable to acknowledge that a competitive project of this importance could possibly be based at a regional university. The Acknowledgements sections of this manuscript and its companion paper [2] both include the following editorially sanctioned statement: "The publication hiatus of more than a decade on this project has been caused by the Australian competitive grants system failing to support a single funding application from M.A.C. after his relocation with the PGRMC1 project from Germany to a regional Australian university." Alas, a decade, and perhaps yet a career, lost to the advancement of science. References 1. Neubauer H, Clare S, Wozny W, Schwall GP, Poznanović S, Stegmann W, Vogel U, Sotlar K, Wallwiener D, Kurek R, Fehm T, Cahill MA. 2008. Breast cancer proteomics reveals correlation between Estrogen Receptor status and differential phosphorylation of PGRMC1. Breast Cancer Res. 10:R85. http://www.ncbi.nlm.nih.gov/pubmed/18922159 2. Thejer BM, Adhikary PP, Teakel SL, Fang J, Weston PA, Gurusinghe S, Anwer AG, Gosnell M, Jazayeri JA, Ludescher M et al: (Cahill MA). 2020. PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease. BMC Molecular and Cell Biology. 21:26. https://www.ncbi.nlm.nih.gov/pubmed/32293262. 3. Hehenberger E, Eitel M, Fortunato SAV, Miller DJ, Keeling PJ, Cahill MA. 2019. Early eukaryotic origins and metazoan elaboration of MAPR family proteins. Molecular Phylogenetics and Evolution. https://www.ncbi.nlm.nih.gov/pubmed/32278076. 4. Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H (III), Spires-Jones TL, Catalano SM. 2014. Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity. PloSOne. 9:e111899. http://www.ncbi.nlm.nih.gov/pubmed/25390692 5. Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, Fillit H, Harrison JE, Schneider LS, Scheltens P, de Haan W, Grundman M, van Dyck CH, Izzo NJ, Catalano SM; Synaptic Health Endpoints Working Group. 2020. The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease. Alzheimers Res Ther. 12(1):21. https://www.ncbi.nlm.nih.gov/pubmed/32122400.
Dr Michael A Cahill
Charles Sturt University
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This page is a summary of: PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth, BMC Molecular and Cell Biology, April 2020, Springer Science + Business Media,
DOI: 10.1186/s12860-020-00256-3.
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