PRL Phosphatases Promote Tumor Progression by Regulating the Level of Intracellular Magnesium
Notice bibliographique
Résumé
The Phosphatase of Regenerative Liver (PRL) enzymes (PRL‐1,‐2,‐3; gene name PTP4A1, PTP4A2, PTP4A3) are members of the protein tyrosine phosphatase family. These enzymes have been identified as key contributors to tumor progression and metastasis in several human cancers, yet the molecular basis of their pro‐oncogenic property is unclear. Using mass spectrometry studies, we identified the CNNM magnesium transporters as key binding partners of PRLs in an evolutionarily conserved complex that regulates the intracellular magnesium concentration. Structural analysis of this complex indicates that the second cystathionine β‐synthase (CBS) domain of CNNM underlines a binding loop unique to the CNNM family that only exists in organisms having PRL orthologs. Mutation of an evolutionarily conserved aspartic acid located in this CBS domain of CNNM3 was able to completely abolish the interaction with PRL‐2 resulting in reduced tumor growth. Also, either the abolishment of complex formation or PRL‐2 knockdown resulted in reduced magnesium transport. Since magnesium is a critical metabolic effector, we confirmed that mitochondrial respiration is altered in cells isolated from PRL2‐null animals and is associated with a lower ATP turnover. This is also consistent with the observed decreased body weight of PRL‐2−/− mice, suggesting that their cellular metabolism is inherently less efficient. As cellular magnesium transport is regulated by intrinsic mechanisms controlling various magnesium transporters and magnesium uptake in cells, we also aimed to examine the involvement of PRLs in the adaptive response related to changes in magnesium availability. Using various cell lines cultured under low magnesium conditions, we observed a decrease in intracellular magnesium levels correlating with a marked increase of PRL‐1 and ‐2 (PRL‐1/2) expression. Although the expression levels of the magnesium transporter CNNM3 remained unchanged after magnesium depletion, we found that the interaction between endogenous PRL‐1/2 and CNNM3 was also markedly increased, indicating a pivotal regulatory role for PRL‐1/2 in the complex to compensate for decreased magnesium availability. On the contrary, upon increasing intracellular magnesium levels by overexpressing the TRPM7 magnesium transporter, we observed a reduction of PRL‐1/2 expression. Consistent with this, using an in vivo reporter mouse model, PRL‐2 tissue expression was upregulated when dietary magnesium was limited. Overall, our findings suggest that PRL phosphatases regulate cellular magnesium levels, essential for cell survival/proliferation, which may explain much of the clinical relationship between PRLs and cancer. Support or Funding Information This research is supported by an operating grant from Canadian Institutes of Health Research (CIHR); CIHR MOP 142497. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».