CrossTalk opposing view: CNNM proteins are not Na+/Mg2+ exchangers but Mg2+ transport regulators playing a central role in transepithelial Mg2+ (re)absorption

Arjona, Francisco J.; Baaij, Jeroen H. F. de

doi:10.1113/jp275249

Cited by 48 publications

(55 citation statements)

References 31 publications

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“…This model was further supported by voltage‐clamp studies using a CNNM3 mutant that is unable to bind the PRLs . This influx mechanism is consistent with the function of CNNM2, which increases the uptake of 25 Mg isotope and where the T568I mutation found in patients was linked with hypomagnesemia caused by impaired magnesium uptake . Funato et al .…”

Section: Cnnm Family: Novel Molecular Players In Prls Functionsupporting

confidence: 56%

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: Cnnm Family: Novel Molecular Players In Prls Functionsupporting

confidence: 56%

Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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“…In turn, the ubiquitous CNNM3 is additionally expressed in the heart, but scarcely in the skeletal muscle [4], while CNNM4 is predominant in the brain, bone marrow, immune system, and especially abundant in the intestinal tract [4,7]. Since their discovery [4,8], the actual function of CNNM proteins has remained controversial [9][10][11][12][13]. For example, CNNM1 appears to act as a cytosolic copper chaperone [14], while CNNM2 and CNNM4 are commonly considered as basolateral Mg 2+ extruders (likely Na + /Mg 2+ exchangers) in the renal and intestinal epithelia, respectively [3,15].…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Giménez-Mascarell

Oyenarte

González‐Recio

et al. 2019

IJMS

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The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.

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“…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).…”

mentioning

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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CrossTalk opposing view: CNNM proteins are not Na⁺/Mg²⁺ exchangers but Mg²⁺ transport regulators playing a central role in transepithelial Mg²⁺ (re)absorption

Cited by 48 publications

References 31 publications

Physiological and oncogenic roles of the PRL phosphatases

Physiological and oncogenic roles of the PRL phosphatases

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

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

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