Evidence That the Protein Phosphatase Activity of PTEN Contributes to Embryonic Development and Tumor Suppression

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a tumor suppressor, the function of which is impaired in many diverse cancers. It has phosphoinositide lipid phosphatase activity by which it suppresses activation of the oncogenic PI3K signaling network but in vitro also displays activity against protein substrates and is able to auto‐dephosphorylate its Thr366 residue. Here we generate germline knock‐in mice expressing PTEN‐Y138L, a mutant enzyme which selectively lacks protein phosphatase activity and retains lipid phosphatase activity. Homozygous Pten Y138L/Y138L mice die in utero before E10.5. Primary MEFs and thymocytes with only a single Pten Y138L allele display normal low levels of AKT phosphorylation indicating effective regulation of PI3K signaling by endogenous PTEN‐Y138L in vivo. Heterozygous Pten +/Y138L mice have reduced overall survival compared to wild‐type littermates and develop tumors in multiple organs. Our data imply that in addition to its lipid phosphatase activity, the protein phosphatase activity of PTEN is also required for normal embryonic development and tumor suppression.