Perspectives On Membrane-associated Progesterone Receptors As Prospective Therapeutic Targets

Abstract

Progesterone receptor membrane components 1 and 2, neudesin, and neuferricin belong to the membraneassociated progesterone receptor (MAPR) family. Recently, sex steroid membrane receptors have gained attention because of their potential involvement in sex hormone-mediated rapid non-genomic effects, which cannot currently be explained by the genomic action of nuclear receptors. Progesterone may increase cell proliferation and survival via nongenomic effects including the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3- kinase (PI3K) pathways through MAPRs. Moreover, the unique expression of MAPRs suggests that they could be used as biomarkers and drug targets for sex steroid-related cancers and other diseases. In this review, we summarize the physiological roles of the MAPRs, provide a comprehensive overview of their progesterone-mediated non-genomic actions, and discuss new insights into their potential as therapeutic targets.

Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions – Focus on Interactions with Cytochromes P450

“…Apart from this, MAPRs interact with an increasing number of different proteins and are involved in a wide variety of cellular functions including cholesterol and steroid homeostasis, cell cycle regulation, cell migration, neurogenesis, autophagy, heme homeostasis and more that are only briefly mentioned but not the focus of this review. Readers interested in these aspects are referred to excellent reviews by others (Losel et al, 2008; Ahmed et al, 2012; Kimura et al, 2012; Neubauer et al, 2013; Cahill et al, 2016; Hasegawa et al, 2016). …”

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

“…Expression is inducible by carcinogens, including dioxin (Selmin et al, 1996), and increased in breast and other tumors, where it contributes to cancer progression (Neubauer et al, 2008;Ruan et al, 2017). Reported physiological functions affected by PGRMC1 include cholesterol/steroid biosynthesis and metabolism (see below), iron homeostasis and heme trafficking by regulating hepcidin expression and ferrochelatase activity (Craven et al, 2007;Li et al, 2016;Piel et al, 2016), promotion of autophagy through interaction with MAP1LC3B (Mir et al, 2013), regulation of cell cycle, proliferation, and cell death (Peluso et al, 2014), maintenance of female reproductive functions in PGRMC1 conditional knock-out mice (McCallum et al, 2016), cell migration and invasion (Sueldo et al, 2015), amyloid beta binding and synaptotoxicity in a mouse model of Alzheimer's disease (Izzo et al, 2014), and others Ahmed et al, 2012;Neubauer et al, 2013;Cahill et al, 2016;Hasegawa et al, 2016). A growing number of studies supports furthermore a role of PGRMC1 in drug response and as potential drug target, e.g., by increasing susceptibility to tyrosine kinase inhibitors (Ahmed et al, 2010), decreasing doxorubicin cytotoxicity (Lin et al, 2015), or mediating atypical antipsychotic drug-induced lipid disturbances (Cai et al, 2015).…”

“…Human PGRMC2 protein is 247 amino acids in length. Despite its structural similarities to PGRMC1, PGRMC2 has been less well studied (Wendler and Wehling, 2013;Hasegawa et al, 2016). Expression appears to be ubiquitous with similar intracellular localization (Chen et al, 2010;Intlekofer and Petersen, 2011).…”

“…Apart from this, MAPRs interact with an increasing number of different proteins and are involved in a wide variety of cellular functions including cholesterol and steroid homeostasis, cell cycle regulation, cell migration, neurogenesis, autophagy, heme homeostasis and more that are only briefly mentioned but not the focus of this review. Readers interested in these aspects are referred to excellent reviews by others Ahmed et al, 2012;Kimura et al, 2012;Neubauer et al, 2013;Cahill et al, 2016;Hasegawa et al, 2016).…”

The evolutionary appearance of signaling motifs in PGRMC1

“…This may be because Neudesin and Neferricin are present in the luminal compartment and secreted extracellularly (2,3,(24)(25)(26)(27)(28), however the presence of some observed phosphorylation events suggests that the MAPR domain of these proteins may also be found in the cytoplasm. The detection of O-N-acetylgalactosamine (O-GalNAc) glycosylation does not necessarily imply an extracellular location for Neudesin, since 14% of O-GalNAc proteins are annotated with nuclear Gene Ontogeny (GO) assignments (29).…”