PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• The phosphoinositide 3-kinase (PI3K)/Akt pathway regulates cell growth and is hyperactivated in cancers.
• Pleckstrin homology domain leucine-rich repeat-containing protein phosphatases (PHLPP) were thought to be tumor suppressors by inhibiting Akt.
• Key aspects of PHLPP function, including metal ion stoichiometry, mechanism, and specificity, remained unknown.

Purpose of the Study:

• To elucidate the enzymatic activity, metal ion binding, and biological role of PHLPP proteins.
• To investigate the proposed tumor suppressor function of PHLPP1 and PHLPP2 using cancer genomics data.
• To understand the evolutionary history and potential non-catalytic functions of PHLPPs.

Main Methods:

• In vitro enzymatic assays to determine PHLPP2 catalytic activity.
• X-ray crystallography to identify bound metal ions in PHLPP2.
• Analysis of cancer genomics data to assess PHLPP1 and PHLPP2 roles in tumorigenesis.
• Phylogenetic and phylogenomic analyses to trace PHLPP evolution and identify coevolving genes.

Main Results:

• PHLPP2 was found to be a pseudophosphatase with no in vitro catalytic activity, possessing a single zinc ion in its active site.
• Cancer genomics data did not support PHLPP1 or PHLPP2 as tumor suppressors.
• Phylogenetic analysis indicated an ancient phosphatase ancestor that lost activity in metazoans; PHLPP2 may retain substrate binding.
• Phylogenomics suggested a scaffolding role for PHLPP2 on membranes.

Conclusions:

• PHLPP2 is a catalytically inactive pseudophosphatase, explaining previous research inconsistencies.
• The proposed tumor suppressor roles of PHLPP1 and PHLPP2 are not supported by current cancer genomics data.
• Future research should explore the non-catalytic, potentially scaffolding, functions of PHLPP1 and PHLPP2.