Physiological and oncogenic roles of the <scp>PRL</scp> phosphatases

Hardy, Serge; Kostantin, Elie; Hatzihristidis, Teri; Zolotarov, Yevgen; Uetani, Noriko; Tremblay, Michel L.

doi:10.1111/febs.14503

Cited by 49 publications

(88 citation statements)

References 214 publications

(393 reference statements)

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“…Phosphatase, which dephosphorylates the kinases and other downstream substrates, plays a key role in controlling signaling transduction and cell fate. Dys-regulation of protein-tyrosine phosphatases is commonly observed in a large amount of cancers [10,11]. The well-known protein-tyrosine phosphatase is Phosphatase and tensin homolog (PTEN) that represents as the second most frequently altered tumor suppressor in cancer, after p53 [12].…”

Section: Discussionmentioning

confidence: 99%

LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway

Zhang

Zhou

2019

Bioscience Reports

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Bladder cancer (BC) is one of the commonest malignancies in the urinary system. Recent evidences have shown that Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) serves as a tumor suppressor in hepatocellular carcinoma and cervical cancer. However, little is known about its function in BC. Here, we aimed to investigate the role of LHPP in BC. We found that LHPP was down-regulated in BC tissues and cells. Knockdown of LHPP promoted the proliferation and growth of BC cells T24 and 5637. Inverse results were observed in SW780 and BIU87 cells with ectopic LHPP expression. LHPP also repressed the glycolysis of BC cells. At the molecular level, LHPP silencing led to enhanced phosphorylation of both AKT and p65, as well as up-regulation of their downstream targets Bcl-2 and Cyclin D1. Inhibition of AKT by MK2206 blunted the increased phosphorylation of p65 caused by LHPP knockdown, suggesting that LHPP silencing activated p65 through AKT. Importantly, p65 inhibitor (caffeic acid phenethyl ester) exhibited larger suppressive effect on the proliferation of LHPP knockdown BC cells as compared with Ctrl cell. Our study demonstrates that LHPP suppresses BC cell growth via inactivating AKT/p65 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway

Zhang

Zhou

2019

Bioscience Reports

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“…CNNMs interact with phosphatases of the regenerating liver (PRL1-3) via the cystathionine-βsynthase (CBS) domain of CNNMs [10] [11]. CNNMs and PRLs have been associated with progression of breast and colon cancers [11] [12].…”

Section: Introductionmentioning

confidence: 99%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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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 protein 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 using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. 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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“…Mg 2+ | PRL phosphatase | uORF | PTP4A | mRNA translation T he phosphatase of regenerating liver (PRL) family is composed of three members (PRL-1, -2, and -3; gene names PTP4A1, PTP4A2, and PTP4A3) of ∼20 kDa with at least 75% amino acid sequence identity shared between them that are highly expressed in a majority of cancers (1). The cyclin M (CNNM) magnesium regulators form an evolutionarily conserved complex with PRLs to regulate intracellular magnesium concentration (2,3).…”

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confidence: 99%

“…The main outcome of PRL overexpression and CNNM complex formation is increased intracellular magnesium, establishing both of these as critical modulators of magnesium homeostasis. However, it is still unclear whether the CNNMs function as magnesium sensors or dual magnesium influx/efflux transporters (1,8,9).…”

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confidence: 99%

Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism

Hardy

Kostantin

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Phosphatases of regenerating liver (PRL-1, PRL-2, and PRL-3, also known as PTP4A1, PTP4A2, and PTP4A3) control magnesium homeostasis through an association with the CNNM magnesium transport regulators. Although high PRL levels have been linked to cancer progression, regulation of their expression is poorly understood. Here we show that modulating intracellular magnesium levels correlates with a rapid change of PRL expression by a mechanism involving its 5′UTR mRNA region. Mutations or CRISPR-Cas9 targeting of the conserved upstream ORF present in the mRNA leader derepress PRL protein synthesis and attenuate the translational response to magnesium levels. Mechanistically, magnesium depletion reduces intracellular ATP but up-regulates PRL protein expression via activation of the AMPK/mTORC2 pathway, which controls cellular energy status. Hence, altered PRL-2 expression leads to metabolic reprogramming of the cells. These findings uncover a magnesium-sensitive mechanism controlling PRL expression, which plays a role in cellular bioenergetics.

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Physiological and oncogenic roles of the PRL phosphatases

Cited by 49 publications

References 214 publications

LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway

LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism

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