PHLPP1 (PH Domain And Leucine Rich Repeat Protein Phosphatase 1)

These findings nominate PHLPP1 as a shared locus for both AD and stroke in individuals of African ancestry. Notably, a genome-wide significant signal in this locus was identified in an admixture mapping study of African Americans (Rajabli et al., 2023). Identification of shared molecular mechanisms between AD and CVD in different populations is useful for understanding the relationship between these two processes in all people.

This "double-edged sword" functionality arises from the high dependency of PHLPP on tissue-specific contexts, such as inflammatory factors and oxidative stress, as well as substrate diversity and dynamic regulation within signaling networks. In this review, we summarize and discuss the complex mechanistic roles of PHLPP in cancer, which is crucial for understanding tumor progression and designing suitable PHLPP-targeted therapeutic strategies in the future.

In vivo studies confirmed that either overexpression of LINC01133 or inhibition of miR-199a-5p suppresses gastric adenocarcinoma cell growth. In summary, LINC01133 re-activation may serve as a potential therapeutic strategy for inhibiting metastasis in gastric adenocarcinoma.

Transcriptome profiling further identified immune-related downstream effectors, including the PH domain leucine-rich repeat protein phosphatase (PHLPP), whose suppression may enhance nuclear factor kappa B (NF-κB) activation via the Akt-IKK pathway. Collectively, these findings uncover a conserved TNF-TNFR-TRAF6 axis in shrimp, providing mechanistic insight into invertebrate antiviral immunity and suggesting a potential genetic target for disease-resistant shrimp breeding.

Since Scribble tethers PHLPP1 and PTEN to antagonize Akt, repression of Scribble induces EMT. In summary, FBL safeguards epithelial integrity, by regulating the expression of Scribble, uncovering an FBL-EZH2 axis in EMT and metastasis.

Furthermore, we highlight emerging regulatory dimensions, including the dephosphorylation of the Par6 complex by phosphatases such as PP2A and PHLPP, which represent novel targets for therapeutic intervention. By integrating these aspects, this review provides a comprehensive and mechanistic framework for understanding the multifaceted roles of Par6 in cancer and underscores its potential as a diagnostic biomarker and therapeutic target.

AKT inhibition (with MK-2206) and PHLPP1 overexpression prominently attenuated the FKBP4-induced increase in HCC cell proliferation and invasion...C-Myc transcriptionally activated-FKBP4 interacted with PHLPP1 to enhance its ubiquitin-mediated degradation, thereby enhancing the AKT pathway and facilitating HCC cell proliferation and invasion. Our findings provide a theoretical basis for targeting FKBP4 in treating HCC.

Gene expression signatures associated with late PDX passages (3rd-5th) were enriched with proliferation and metabolic reprogramming-related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4+ T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.

Distinct differences in tumor-adherent microbiota, gene expression and immune response profiles were observed. Notably, IBD-CRC patients demonstrated the poorest prognosis depending on microbe-host gene interaction highlighting potential biomarkers for disease prognosis and treatment strategies.

Finally, using phylogenomics, we identify coevolving genes consistent with a scaffolding role for PHLPP2 on membranes. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a focus on the noncatalytic roles of PHLPP1 and PHLPP2.

This study concludes that PHLPP1 has the capability to reduce the expression of cancer stemness genes by negatively regulating the AKT signaling pathway. Therefore, these findings may pave the way for discoveries in the context of cancer stemness and future strategies for developing effective treatment options for TNBC patients.