Recent advances in PHLPP1 and PHLPP2 research: an update in the heart

Abstract

In recent years, pleckstrin homology domain leucine-rich repeat protein phosphatase-1 (PHLPP1) and 2 (PHLPP2) have emerged as key players in regulating various survival signaling pathways, including Akt, and contribute towards cardiovascular disease development. This review highlights the diverse mechanisms regulating PHLPP1/2 at transcriptional, translational, and post-translational levels and discusses their role in cardiovascular function and disease. We further explore the therapeutic potential of targeting PHLPP1/2 using small molecule inhibitors, peptide inhibitors, microRNAs, long noncoding RNAs, and natural compounds. While the divergent roles of PHLPP1 and PHLPP2 in maintaining cellular homeostasis and their dysregulation in cancer and other diseases are well documented, their regulation and downstream targets in the heart under normal and pathological states remain unclear. Future studies are warranted to discover the regulatory mechanisms of PHLPP1/2, identify novel cardiac stress-regulated substrate kinases and binding partners, and develop therapies that target these phosphatases independently for clinical translation.