PHLPP is neither a Phosphatase nor a Tumor Suppressor

PH domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/PHLPP2) have, for more than 20 years, been described as Akt phosphatases and tumor suppressor genes. Approximately 200 PubMed-indexed articles have been published on the topic, including efforts to pharmacologically inhibit PHLPP in disease settings. A recent study, however, presents evidence that PHLPP is actually a pseudophosphatase with no catalytic activity. These observations question its reported role in cancer. The designation of PHLPP1 and PHLPP2 as pseudophosphatases necessitates both a critical examination of the literature and new hypotheses for the biological function of these ancient proteins. Here, we review the emergence of PHLPP1 and PHLPP2 as cellular signal transducers, critically examine the evidence for their reported phosphatase activity and tumor suppressor functions, and propose steps to elucidate their biological functions.