PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many human cancers. Pleckstrin homology domain leucine-rich repeat-containing protein phosphatases (PHLPP), two paralogous members of the metal-dependent protein phosphatase family, have been reported as negative regulators of Akt signaling and, therefore, tumor suppressors. However, the stoichiometry and identity of the bound metal ion(s), mechanism of action, and enzymatic specificity of these proteins are not known. Seeking to fill these gaps in our understanding of PHLPP biology, we unexpectedly found that PHLPP2 has no catalytic activity in vitro. Instead, we found that PHLPP2 is a pseudophosphatase with a single zinc ion bound in its catalytic center. Furthermore, we found that cancer genomics data do not support the proposed role of PHLPP1 or PHLPP2 as tumor suppressors. Phylogenetic analyses revealed an ancestral phosphatase that arose more than 1,000 Mya, but that lost activity at the base of the metazoan lineage. Surface conservation indicates that while PHLPP2 has lost catalytic activity, it may have retained substrate binding. Finally, using phylogenomics, we identify coevolving genes consistent with a scaffolding role for PHLPP2 on membranes. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a focus on the noncatalytic roles of PHLPP1 and PHLPP2.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-04-01
DOI
https://doi.org/10.1073/pnas.2417218122
Citations
2
Primary Topic
Protein Tyrosine Phosphatases
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article
Field-Weighted Citation Impact
1.61

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article

PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

Stephan Hann, David Haselbach, Egon Ogris, Todor Dudev et al.
2 citations
Proceedings of the National Academy of Sciences
Protein Tyrosine Phosphatases
1.61
article

PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

Stephan Hann, David Haselbach, Egon Ogris, Todor Dudev, Silvia Angelova, Dorothea Anrather, Thomas A. Leonard, Sumire Antonioli, Irina Grishkovskaya, Katharina M. Siess, Christoph Bock, Markus Hartl, Nicholas A. T. Irwin, Nikoleta Kircheva, Jiri Veis, Martin Leeb, Linda Truebestein, Bojan Žagrović, Luis Miguel Cerron-Alvan, Vanessa Meier, Tarik Husremović, Fran Miočić-Stošić, Lucas Piëch, Andreas Brandstätter, Karoline Wenzl
article en
2 citations

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many human cancers. Pleckstrin homology domain leucine-rich repeat-containing protein phosphatases (PHLPP), two paralogous members of the metal-dependent protein phosphatase family, have been reported as negative regulators of Akt signaling and, therefore, tumor suppressors. However, the stoichiometry and identity of the bound metal ion(s), mechanism of action, and enzymatic specificity of these proteins are not known. Seeking to fill these gaps in our understanding of PHLPP biology, we unexpectedly found that PHLPP2 has no catalytic activity in vitro. Instead, we found that PHLPP2 is a pseudophosphatase with a single zinc ion bound in its catalytic center. Furthermore, we found that cancer genomics data do not support the proposed role of PHLPP1 or PHLPP2 as tumor suppressors. Phylogenetic analyses revealed an ancestral phosphatase that arose more than 1,000 Mya, but that lost activity at the base of the metazoan lineage. Surface conservation indicates that while PHLPP2 has lost catalytic activity, it may have retained substrate binding. Finally, using phylogenomics, we identify coevolving genes consistent with a scaffolding role for PHLPP2 on membranes. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a focus on the noncatalytic roles of PHLPP1 and PHLPP2.

Proceedings of the National Academy of SciencesVol. 122(14)
University of Vienna (AT), Gregor Mendel Institute of Molecular Plant Biology (AT), Austrian Academy of Sciences (AT), Austrian Research Institute for Artificial Intelligence (AT), Research Institute of Molecular Pathology (AT), Bulgarian Academy of Sciences (BG), Max Perutz Labs (AT), Institute of Art (PL), Vienna Biocenter (AT), University of Chemical Technology and Metallurgy (BG), Czech Academy of Sciences, Institute of Analytical Chemistry (CZ), Sofia University "St. Kliment Ohridski" (BG), Medical University of Vienna (AT), BOKU University (AT)
Österreichischen Akademie der Wissenschaften, Austrian Science Fund, Universität Wien, OeAD-GmbH, Medizinische Universität Wien, Bulgarian Academy of Sciences, Universität für Bodenkultur Wien, University of Chemical Technology and Metallurgy, Ústav analytické chemie, Akademie Věd České Republiky
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Openalex Percentile: Top 18%
Protein Tyrosine Phosphatases
1.61
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