Biology subjects

Cahill, M. A.

Publications and source records attributed to Cahill, M. A..

3 recordsLinked to original sources

bioRxiv2019

PGRMC1 phosphorylation status and cell plasticity 1: glucose metabolism, mitochondria, and mouse xenograft tumorigenesis

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. Here, 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 mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.

cancer biology↗

bioRxiv2019

PGRMC1 phosphorylation status and cell plasticity 2: genomic integrity and CpG methylation

Progesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation. Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture. A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

cell biology↗

bioRxiv2019

Early eukaryotic origins and metazoan elaboration of MAPR family proteins

BackgroundThe membrane-associated progesterone receptor (MAPR) family consists of heme-binding proteins containing a cytochrome b5 (cytb5) domain characterized by the presence of a MAPR-specific interhelical insert region (MIHIR) between helices 3 and 4 of the canonical cytb5-domain fold. Animals possess three MAPR families (PGRMC-like, Neuferricin and Neudesin).\n\nResultsHere we show that all animal MAPR families were already present in the common ancestor of the Opisthokonta (comprising animals and fungi as well as related protistan taxa). All three MAPR genes acquired extensions C-terminal to the cytb5 domain, either before or with the evolution of animals. The archetypical MAPR protein, progesterone receptor membrane component 1 (PGRMC1), contains phosphorylated tyrosines Y139 and Y180. The combination of Y139/Y180 appeared in the common ancestor of Cnidaria and bilaterally symmetrical animals, along with an early embryological organizer and synapsed neurons, and is strongly conserved in all bilateral animals. A predicted protein interaction motif in the PGRMC1 MIHIR is potentially regulated by Y139 phosphorylation. A multilayered model of animal MAPR function acquisition includes some pre-metazoan functions (e.g., heme binding and cytochrome P450 interactions) and some acquired animal-specific functions that involve regulation of strongly conserved protein interaction motifs acquired by early-branching animals.\n\nConclusionsThis study provides a conceptual framework for future studies, against which PGRMC1s multiple functions can perhaps be stratified and functionally dissected. In accompanying papers we show that mutational perturbation of PGRMC1 phosphorylation status of the Y180 motif is associated with dramatic changes cell pasticity assayed by protein abundances, cell morphology, mitochondrial function, genomic stability, and epigenetic status, with pathways analysis associating Y180 mutation with processes related to organizer function. These combined works reveal previously unrecognized involvement of PGRMC1 in foundational animal processes of great relevance to disease.

evolutionary biology↗