{"doi":"10.1016/j.celrep.2025.116722","title":"Liprin-α1 enhances PHLDB3 oncogenic function in colorectal cancer via activation of mTORC2-AKT1 pathway","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.","journal":"Cell Reports","year":2025,"id":585811,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":336454,"name":"Bo Cao","orcid":"0000-0002-4933-6424","position":1,"is_corresponding":false},{"id":1193439,"name":"Li Li","orcid":"0000-0003-2247-5720","position":2,"is_corresponding":false},{"id":970145,"name":"Hee‐Won Park","orcid":"0000-0002-7434-6675","position":3,"is_corresponding":false},{"id":336460,"name":"Shelya X. Zeng","orcid":"0000-0001-5195-9420","position":4,"is_corresponding":false},{"id":598424,"name":"Hua Lu","orcid":"0000-0003-1199-6678","position":5,"is_corresponding":false},{"id":1078449,"name":"Hyun Min Ko","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:59:24.273134Z","pmid":"41405991","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}