{"doi":"10.1101/2021.03.27.437291","title":"aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis","abstract":"Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatments. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory and anti-apoptotic activities, which is facilitated by co-receptors. We showed that aPC-activated PAR1 signals preferentially via b-arrestin-2 (b-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to enhance barrier protection. However, the mechanisms by which aPC/PAR1 promotes other cytoprotective responses are poorly understood. Here we define a novel β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. We show that PAR1 and S1PR1 co-exist in caveolin-1-rich microdomains basally and aPC markedly increases S1PR1-caveolin-1 co-association. Moreover, aPC stimulates b-arr2-dependent SphK1 activation independent of Dvl2, which is critical for S1PR1 transactivation. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete b-arr2-driven signaling pathways in caveolae.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223800,"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":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":475851,"name":"Cierra A. Birch","orcid":null,"position":1,"is_corresponding":false},{"id":88595,"name":"Dequina Nicholas","orcid":"0000-0003-4996-2190","position":2,"is_corresponding":false},{"id":825979,"name":"Metzli Cisneros-Aguirre","orcid":null,"position":3,"is_corresponding":false},{"id":825604,"name":"Anand V. Patwardhan","orcid":"0000-0003-1928-8510","position":4,"is_corresponding":false},{"id":459928,"name":"Buxin Chen","orcid":"0000-0002-5884-8173","position":5,"is_corresponding":false},{"id":465532,"name":"Neil Grimsey","orcid":"0000-0002-0481-4920","position":6,"is_corresponding":false},{"id":825980,"name":"Patrick K. Gomez-Menzies","orcid":null,"position":7,"is_corresponding":false},{"id":699951,"name":"Huilan Lin","orcid":null,"position":8,"is_corresponding":false},{"id":699950,"name":"Luisa J. Coronel","orcid":null,"position":9,"is_corresponding":false},{"id":426816,"name":"Mark A. Lawson","orcid":"0000-0003-2303-3086","position":10,"is_corresponding":false},{"id":561511,"name":"Hemal H. Patel","orcid":"0000-0001-6722-9625","position":11,"is_corresponding":false},{"id":247561,"name":"JoAnn Trejo","orcid":"0000-0003-4405-6228","position":12,"is_corresponding":false},{"id":328116,"name":"Olivia Molinar‐Inglis","orcid":"0000-0002-4974-9608","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:54:14.760456Z","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":[]}