PRL Phosphatases Promote Tumor Progression by Regulating the Level of Intracellular Magnesium
Bibliographic record
Abstract
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 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".