PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

• 成果类型: Article
• 署名作者: Husremovic, Tarik; Meier, Vanessa; Piech, Lucas; Siess, Katharina M.; Antonioli, Sumire; Grishkovskaya, Irina; Kircheva, Nikoleta; Angelova, Silvia E.; Wenzl, Karoline; Brandstaetter, Andreas; Veis, Jiri; Miocic-Stosic, Fran; Anrather, Dorothea; Hartl, Markus; Truebestein, Linda; Cerron-Alvan, Luis M.; Leeb, Martin; Zagrovic, Bojan; Hann, Stephan; Bock, Christoph; Ogris, Egon; Dudev, Todor; Irwin, Nicholas A. T.; Haselbach, David; Leonard, Thomas A.
• 署名单位: Medical University of Vienna; University of Vienna; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); Medical University of Vienna; Vienna Biocenter (VBC); University of Vienna; Medical University of Vienna; Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Bulgarian Academy of Sciences; University of Chemical Technology & Metallurgy - Bulgaria; BOKU University; University of Vienna; Medical University of Vienna; University of Vienna; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); University of Vienna; University of Vienna; Austrian Academy of Sciences; Medical University of Vienna; University of Sofia; Austrian Academy of Sciences; Vienna Biocenter (VBC); Gregor Mendel Institute of Molecular Plant Biology (GMI)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9658
• DOI: 10.1073/pnas.24172181221
• 发表日期: 2025-04-08
• 关键词: pleckstrin homology domain; protein phosphatase; adenylyl-cyclase; 3rd metal; akt; kinase; phosphorylation; activation; survival; association

摘要

The phosphoinositide 3- kinase (PI3K) pathway is a major regulator of cell and organisAkt, 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.