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