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.

Choose your partners for the next dance: implied PGRMC1 roles in membrane trafficking and mitochondrial modulation

“…This was associated with elevated abundance of some actin-cytoskeletal proteins, increased motility, and dramatic effects on mitochondrial function (4), perhaps reflecting processes underlying those implicated in decidualization. The effect was dependent on Rho-associated protein kinase 1 and accompanied by Y180-dependent PI3K/Akt pathway activity (4). In another study we found that the MAPR interhelical insertion region (MIHIR) in the PGRMC1 Cytb5 domain contains a predicted coiled-coil motif (Fig.…”

“…Because phosphorylation plays an important part in PGRMC1 biology (2,4), and because Salsano et al used bacterially expressed and nonphosphorylated glutathione-S-transferase (GST) labeled PGRMC1 as bait in the coimmunoprecipitation studies, it is difficult to interpret whether all particular identified coprecipitated proteins from cell lysates actually interact with PGRMC1 in cells under the given experimental condition examined, or whether perhaps some interactions with endogenous PGRMC1 were attenuated by treatment, making more protein available to interact with the GST bait protein, or vice versa (Fig. 1).…”