PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms

Uetani, Noriko; Hardy, Serge; Gravel, Simon-Pierre; Kiessling, Silke; Pietrobon, Adam; Wong, Nau Nau; Chénard, Valérie; Cermakian, Nicolas; St‐Pierre, Julie; Tremblay, Michel L.

doi:10.1172/jci.insight.91722

Cited by 18 publications

(29 citation statements)

References 64 publications

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“…Compared to PRL-1 and PRL-3, the ubiquitously expressed PRL-2 plays more striking roles in various physiological processes. PRL-2 KO mice display several striking features including growth retardation, and splenic and testicular hypoplasia [43,59,61,62]. As mentioned earlier, PRL-2 KO male mice display impaired reproductive ability due to defects in spermatogenesis [59].…”

Section: Physiological Function Of the Prlslessons From Knockout Modelsmentioning

confidence: 67%

“…This Smad3/4 complex binds two sites in the promoter of PRL-3 to suppress expression [42] and may be an important mechanism through which TGFb suppresses metastasis in colon. A novel transcriptional control mechanisms reported for the PRL genes and their binding partners, the CNNMs (see below), is that their expression is under circadian control through several circadian associated transcription factors including Clock, Bmal1, Per1/2, and others [43]. Expression of the PRLs follows a magnesium-dependent circadian pattern and a mouse knockout of PRL-2 highlights a key role for this phosphatase in circadian control of behavior and metabolism [43].…”

Section: Presence Of Prl Homologs In the Tree Of Life And Human Parasmentioning

confidence: 99%

“…It is still undetermined if CNNM2 is able to transport magnesium directly or act as an intracellular ion sensor . The subcellular localization of CNNM3 was similarly shown to be at the plasma membrane, but a fainter signal was also observed intracellularly . Mutation in aspartic acid residue (D426A) of CNNM3, which is involved in PRL binding, decreased its electrophysiological current and affects the selectivity of CNNM3 to magnesium, iron, copper, and cobalt through voltage‐clamp assay .…”

Section: Cnnm Family: Novel Molecular Players In Prls Functionmentioning

confidence: 99%

“…A novel transcriptional control mechanisms reported for the PRL genes and their binding partners, the CNNMs (see below), is that their expression is under circadian control through several circadian associated transcription factors including Clock, Bmal1, Per1/2, and others [43]. Expression of the PRLs follows a magnesium-dependent circadian pattern and a mouse knockout of PRL-2 highlights a key role for this phosphatase in circadian control of behavior and metabolism [43]. These observations are consistent with the regulation of PRLs expression by extracellular magnesium levels in multiple cell lines [44] and also in vivo by dietary magnesium in a PRL-2 reporter mouse models [45], thus establishing the PRLs as important regulators of magnesium homeostasis.…”

Section: Presence Of Prl Homologs In the Tree Of Life And Human Parasmentioning

confidence: 99%

“…In addition to loss of body weight, PRL-2 KO mice showed sex-dependent differences in fat and muscle composition [43]. Interestingly, expression of PRL-2 was regulated in a sex-and circadian timedependent manner in brown adipose tissue, where chemical energy is converted into heat to maintain body temperature [43]. Consistently, thermogenic ability and circadian energy metabolism were altered in a sex-dependent manner in PRL-2 KO mice and the ratio for uncoupled respiration was increased in PRL-2-KO mouse embryonic fibroblasts.…”

Section: Physiological Function Of the Prlslessons From Knockout Modelsmentioning

confidence: 99%

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Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL-1, -2, -3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport.

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Section: Physiological Function Of the Prlslessons From Knockout Modelsmentioning

confidence: 67%

Section: Presence Of Prl Homologs In the Tree Of Life And Human Parasmentioning

confidence: 99%

Section: Cnnm Family: Novel Molecular Players In Prls Functionmentioning

confidence: 99%

Section: Presence Of Prl Homologs In the Tree Of Life And Human Parasmentioning

confidence: 99%

Section: Physiological Function Of the Prlslessons From Knockout Modelsmentioning

confidence: 99%

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Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity

Penafuerte

Perez-Quintero

Vinette

et al. 2017

Current Topics in Microbiology and Immunology

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The family of protein tyrosine phosphatases (PTPs) includes 107 genes in humans that are diverse in their structures and expression profiles. The majority are present in immune cells and play various roles in either inhibiting or promoting the duration and amplitude of signaling cascades. Several PTPs, including TC-PTP (PTPN2) and SHP-1 (PTPN6), have been recognized as being crucial for maintaining proper immune response and self-tolerance, and have gained recognition as true immune system checkpoint modulators. This chapter details the most recent literature on PTPs and immunity by examining their known functions in regulating signaling from either established checkpoint inhibitors or by their intrinsic properties, as modulators of the immune response. Notably, we review PTP regulatory properties in macrophages, antigen-presenting dendritic cells, and T cells. Overall, we present the PTP gene family as a remarkable source of novel checkpoint inhibitors wherein lies a great number of new targets for immunotherapies.

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ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2021

Cell. Mol. Life Sci.

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Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like GTPase 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction between CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 and CNBH domains. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the endoplasmic reticulum, Golgi apparatus and the plasma membrane. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

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PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms

Cited by 18 publications

References 64 publications

Physiological and oncogenic roles of the PRL phosphatases

Physiological and oncogenic roles of the PRL phosphatases

Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

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