{"doi":"10.1038/s41418-024-01414-2","title":"AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis","abstract":null,"journal":"Cell Death & Differentiation","year":2025,"id":642562,"datarank":0.7186414099452064,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.18968733125278217,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.18968733125278217,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":29,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1671451,"name":"Shanliang Zheng","orcid":"0000-0002-4917-9932","position":1,"is_corresponding":false},{"id":1671452,"name":"Guixue Hou","orcid":"0000-0003-0342-9593","position":2,"is_corresponding":false},{"id":1671453,"name":"Junren Dai","orcid":null,"position":3,"is_corresponding":false},{"id":98633,"name":"Yanan Zhao","orcid":"0000-0002-1532-3641","position":4,"is_corresponding":false},{"id":1294743,"name":"Fan Yang","orcid":"0000-0003-3671-4745","position":5,"is_corresponding":false},{"id":1671454,"name":"Zhiyuan Xiang","orcid":null,"position":6,"is_corresponding":false},{"id":165152,"name":"Wenxin Zhang","orcid":"0000-0002-2516-0954","position":7,"is_corresponding":false},{"id":1285948,"name":"Xingwen Wang","orcid":"0000-0003-0480-8835","position":8,"is_corresponding":false},{"id":1671457,"name":"Yafan Gong","orcid":null,"position":9,"is_corresponding":false},{"id":697735,"name":"Li Li","orcid":"0000-0001-6598-6358","position":10,"is_corresponding":false},{"id":921484,"name":"Ning Zhang","orcid":"0000-0003-2095-5261","position":11,"is_corresponding":false},{"id":816397,"name":"Ying Hu","orcid":"0000-0003-2469-5604","position":12,"is_corresponding":false},{"id":698457,"name":"Hao Liu","orcid":"0000-0003-3028-1432","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis","abstract":"Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.","is_dataset_classified":null,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39537840","pmcid":"PMC11893801","openalex_id":"https://openalex.org/W4404312849","authors":[],"funders":[],"total_grants":0,"fwci":8.4359,"citation_percentile":0.98432744,"influential_citations":0,"citation_trend":[{"year":2025,"count":12},{"year":2026,"count":18}],"oa_status":"green","license":"https://www.springernature.com/gp/researchers/text-and-data-mining","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11893801/","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11893801/","host_type":"repository"},{"url":"https://www.nature.com/articles/s41418-024-01414-2.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41418-024-01414-2","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41418-024-01414-2","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39537840","host_type":"repository"}],"fields_of_study":["Ferroptosis and cancer prognosis","Endoplasmic Reticulum Stress and Disease","RNA modifications and cancer"],"mesh_terms":["Ferroptosis","Animals","Endoplasmic Reticulum","Humans","Membrane Proteins","Mitochondria","Neoplasms","Phosphorylation","Signal Transduction","Cyclic AMP-Dependent Protein Kinases","HSP70 Heat-Shock Proteins","Cell Line, Tumor","Mice","A Kinase Anchor Proteins"],"keywords":["Endoplasmic reticulum","Phosphorylation","Mitochondrion","Cell biology","Chemistry","Membrane","Cancer cell","Cancer research","Cancer","Biochemistry","Biology","Medicine","Internal medicine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-08T00:14:28.298683Z","pmid":null,"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":[]}