Liprin-α1 enhances PHLDB3 oncogenic function in colorectal cancer via activation of mTORC2-AKT1 pathway.

Colorectal cancer (CRC) progression is driven by aberrant activation of oncogenic pathways, including AKT1, which requires mTORC2-mediated phosphorylation at Ser473. This study identifies PHLDB3 and Liprin-α1 as key regulators of RICTOR-dependent, mTORC2-mediated AKT1 signaling, independently of p53. PHLDB3 interacts with RICTOR to enhance AKT1 phosphorylation and promote tumor progression. In p53-null CRC cells, PHLDB3 knockdown reduces AKT1 activation, whereas PHLDB3 overexpression increases it. Liprin-α1 stabilizes PHLDB3 by limiting its proteasomal degradation, thereby maintaining mTORC2 activity. Liprin-α1 depletion lowers PHLDB3 levels and impairs AKT1 signaling, whereas Liprin-α1 overexpression boosts PHLDB3-mediated AKT1 activation and CRC cell proliferation. Importantly, the Liprin-α1-PHLDB3 axis depends on RICTOR, underscoring a hierarchical regulation essential for AKT1 activation. PHLDB3 is significantly overexpressed in CRC and is associated with poor prognosis. These findings reveal a Liprin-α1-PHLDB3-mTORC2-AKT1 signaling pathway important for CRC growth and present this pathway as a promising therapeutic target in CRC.