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

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

  • Cell Rep. 2025 Dec 16;45(1):116722. doi: 10.1016/j.celrep.2025.116722.
Hyun Min Ko 1,  Bo Cao 1,  Li Li 2,  Hee-Won Park 3,  Shelya X Zeng 4,  Hua Lu 5
Affiliations

Affiliations

  • 1 Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
  • 2 Laboratory of Translational Cancer Research, Ochsner Clinic Foundation, 1516 Jefferson Highway, New Orleans, LA 70201, USA.
  • 3 Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Electronic address: [email protected].
  • 4 Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Electronic address: [email protected].
  • 5 Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Electronic address: [email protected].
PMID: 41405991 DOI: 10.1016/j.celrep.2025.116722
Abstract

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.

Keywords

AKT1; CP: Cancer; Liprin-α1; PHLDB3; RICTOR; and CRC; mTORC2.

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