Biochem Pharmacol. 2026 Oct 25:118573. doi: 10.1016/j.bcp.2026.118573. Online ahead of print.
ABSTRACT
PHLPP1 and PHLPP2 (pleckstrin homology-domain leucine-rich-repeat protein phosphatases) are multidomain signaling proteins that have been associated with the regulation of AKT phosphorylation in several cellular contexts. PHLPP1 and PHLPP2 have historically been classified as PP2C-family phosphatases that terminate AKT signaling. Recent biochemical evidence challenges this interpretation for PHLPP2, which showed no detectable phosphatase activity in vitro and contained a single Zn2⁺ ion in its catalytic center, raising the possibility that it functions as a signaling pseudophosphatase or scaffold. While traditionally characterized as tumor suppressors, emerging evidence reveals that PHLPP isoforms possess distinct, non-redundant roles at the interface of metabolism, cardiovascular integrity, and regulated cell death (RCD). This functional diversity introduces a complex biochemical paradox, in which the tight regulation of these phosphatases dictates divergent pathological and protective outcomes depending on the cellular microenvironment. This review provides a comprehensive analysis of the structural divergence between PHLPP1 and PHLPP2, emphasizing how the PHLPP1-specific N-terminal extension and PDZ-binding motif contribute to spatial signaling specificity and preferential targeting of AKT2/3, while PHLPP2 exhibits preference toward AKT1/3, reflecting isoform-dependent differences in regulatory architecture. The review asks how two decades of cellular and disease evidence should be reinterpreted if PHLPP proteins, particularly PHLPP2, function as signaling pseudoenzymes or scaffolds rather than conventional AKT phosphatases. Finally, we evaluate the therapeutic landscape, focusing on small-molecule inhibitors and cell-penetrating peptides designed to modulate the PHLPP-AKT interface as a programmable node for dual-target therapies.
PMID:42927860 | DOI:10.1016/j.bcp.2026.118573