PHLPP2, short for PH domain and leucine rich repeat protein phosphatase 2, is a member of the PHLPP family of phosphatases. It is known to suppress cell growth by inhibiting proliferation or promoting apoptosis, and is involved in multiple signaling pathways. Key pathways include the AKT signaling pathway, where it acts as an Akt Ser473 phosphatase, and it also interacts with the AMP-activated protein kinase (AMPK) pathway [1,2]. PHLPP2 has been implicated in the regulation of various biological processes relevant to health and disease, including glucose and lipid homeostasis, and response to metabolic stress.

In adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice, reduced adiposity and improved whole-body glucose tolerance were observed with high-fat diet feeding. This was due to increased HSL phosphorylation leading to increased lipolysis, and subsequent oxidation of mobilized fatty acids, which increased PPARα-dependent adiponectin secretion and ameliorated obesity-induced fatty liver [1]. In T-leukemia cells, silencing PHLPP2 prolonged survival under severe glucose limitation by promoting a switch to AMPK-mediated fatty acid oxidation for energy generation [2]. In hepatocellular carcinoma, the E3 ubiquitin ligase TRIM22 triggers cellular senescence by targeting PHLPP2 for degradation, activating the AKT-p53-p21 signaling pathway [3].

In conclusion, PHLPP2 plays essential roles in regulating glucose and lipid metabolism, response to metabolic stress, and cellular senescence in cancer cells. The use of gene knockout mouse models, such as the A-PHLPP2 mice, has been crucial in uncovering these functions, providing insights into its potential as a therapeutic target in diseases related to obesity-induced fatty liver, cancer, and metabolic disorders.