PGRMC1 has crucial roles in animal biology and disease

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Firstly, as elaborated upon in the Kudos description (https://link.growkudos.com/1e1cu8d86io) of the companion paper [1], I dedicate this publication to the ground-breaking work performed by my colleagues from ProteoSys Ag in Mainz, Germany, between 2000 and 2007. It was there that we used our proprietary ProteoTope technology to first discover differential PGRMC1 phosphorylation between estrogen receptor positive and negative breast tumours which we patented by 2005 (WO2005078124) and published in 2008 [2]. In the companion paper, we show that the mutations we used in this current study induced very strong differences in protein abundance, basic glucose metabolism, mitochondrial shape and function, and ability to form tumours [1]. In another recent publication [3] we showed that Y180 first appeared in evolution at the stage of the last eumetazoan common ancestor (LEUMCA), the ancestor that gave rise to cnidarians (jellyfish, hydras, corals, and sea anemones), and all bilaterally symmetrical animals, including insects, worms, molluscs, spiders, etc. The LEUMCA was the first organism to evolve an embryological gastrulation organiser, which is the centre that initiates the cascade of events that gives rise to processes that define and lay down the body plans of various animals as they grow. The LEUMCA was the first organism to develop a specialised gut epithelium, and nerves with synapses which we inherited. In other words, we are built upon PGRMC1 Y180, and our big-brained nervous system is intrinsically associated with PGRMC1 function. At the embryological stage of the gastrulation organiser, mammals have what are called embryonic stem cells, which can proliferate and differentiate into all other cell types in the adult body. These stem cells may resemble the organisational level of cells of the LEUMCA eumetazoan ancestor that first developed the gastrulation organiser. Embryonic stem cells have a high level of genomic methylation: i.e. the genes are mostly packed away in highly methylated regions of chromosomes, and only stem cell genes are open and 'on'. When we mutated Y180, the methylation level of the genome dramatically increased. It was as if the cultured cancer cells that we worked with were trying to revert to the genomic state of organisation before the LEUMCA, before animals acquired Y180. In other words phosphorylation of PGRMCI tyrosine 180, which was first acquired by the LEUMCA, may be required to maintain the state of differentiation of cells in the adult state. Our results do not show this because more work would need to be done. However our results are consistent with that. In any event, PGRMC1 is shaping to be a skyscraper on the horizon of important animal proteins. References 1. Thejer BM, Adhikary PP, Kaur A, Teakel SL, Van Oosterum A, Seth I, Pajic M, Hannan KM, Pavy M, Poh P et al: (Cahill MA). 2020. PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth. BMC Molecular and Cell Biology. 21:24. https://www.ncbi.nlm.nih.gov/pubmed/32245408. 2. 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 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.

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