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Phosphatase, pseudo-phosphatase, or both? Understanding PRL oncogenicity

A Correction to this article was published on 10 March 2021

This article has been updated

Summary

Phosphatases of regenerating liver (PRL1–3) are among the most oncogenic protein phosphatases but their mechanism of action is poorly understood. Multiple substrates have been proposed as well as a non-catalytic function regulating magnesium transport. Our recent identification of a catalytically inactive PRL mutant that retains oncogenicity in a mouse model promises to resolve the question of whether PRLs act as phosphatases or pseudo-phosphatases in different cancer models.

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Fig. 1: PRL3 acts as a pseudo-phosphatase.

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References

  1. Diamond, R. H., Cressman, D. E., Laz, T. M., Abrams, C. S. & Taub, R. PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Mol. Cell. Biol. 14, 3752–3762 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Saha, S., Bardelli, A., Buckhaults, P., Velculescu, V. E., Rago, C., St Croix, B. et al. A phosphatase associated with metastasis of colorectal cancer. Science 294, 1343–1346 (2001).

    Article  CAS  Google Scholar 

  3. Funato, Y., Yamazaki, D., Mizukami, S., Du, L., Kikuchi, K. & Miki, H. Membrane protein CNNM4-dependent Mg2+ efflux suppresses tumor progression. J. Clin. Investig. 124, 5398–5410 (2014).

    Article  Google Scholar 

  4. Hardy, S., Uetani, N., Wong, N., Kostantin, E., Labbe, D. P., Begin, L. R. et al. The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene 34, 986–995 (2015).

    Article  CAS  Google Scholar 

  5. Gulerez, I., Funato, Y., Wu, H., Yang, M., Kozlov, G., Miki, H. et al. Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis. EMBO Rep. 17, 1890–1900 (2016).

    Article  CAS  Google Scholar 

  6. Kozlov, G., Cheng, J., Ziomek, E., Banville, D., Gehring, K. & Ekiel, I. Structural insights into molecular function of the metastasis-associated phosphatase PRL-3. J. Biol. Chem. 279, 11882–11889 (2004).

    Article  CAS  Google Scholar 

  7. Funato, Y. & Miki, H. Reversible oxidation of PRL family protein-tyrosine phosphatases. Methods 65, 184–189 (2014).

    Article  CAS  Google Scholar 

  8. Zhang, H., Kozlov, G., Li, X., Wu, H., Gulerez, I. & Gehring, K. PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3. Sci. Rep. 7, 48 (2017).

    Article  Google Scholar 

  9. Gimenez-Mascarell, P., Oyenarte, I., Hardy, S., Breiderhoff, T., Stuiver, M., Kostantin, E. et al. Structural basis of the oncogenic interaction of phosphatase PRL-1 with the magnesium transporter CNNM2. J. Biol. Chem. 292, 786–801 (2017).

    Article  CAS  Google Scholar 

  10. Kozlov, G., Funato, Y., Chen, Y. S., Zhang, Z., Illes, K., Miki, H. et al. PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth. J. Biol. Chem. 295, 11682–11692 (2020).

    Article  CAS  Google Scholar 

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K.G. and H.M. contributed to the writing, revision, and approval of this manuscript.

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Correspondence to Kalle Gehring.

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This work was supported by the Natural Sciences and Engineering Research Council of Canada.

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Gehring, K., Miki, H. Phosphatase, pseudo-phosphatase, or both? Understanding PRL oncogenicity. Br J Cancer 124, 1035–1036 (2021). https://doi.org/10.1038/s41416-020-01194-9

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