{"doi":"10.1016/j.jbc.2023.105408","title":"Spleen Tyrosine Kinase phosphorylates VE-cadherin to cause endothelial barrier disruption in acute lung injury","abstract":"Increased endothelial cell (EC) permeability is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Tyrosine phosphorylation of VE-cadherin is a key determinant of EC barrier disruption. However, the identity and role of tyrosine kinases in this context are incompletely understood. Here we report that Spleen Tyrosine Kinase (Syk) is a key mediator of EC barrier disruption and lung vascular leak in sepsis. Inhibition of Syk by pharmacological or genetic approaches, each reduced thrombin-induced EC permeability. Mechanistically, Syk associates with and phosphorylates VE-cadherin to cause EC permeability. To study the causal role of endothelial Syk in sepsis-induced ALI, we used a remarkably efficient and cost-effective approach based on gene transfer to generate EC-ablated Syk mice. These mice were protected against sepsis-induced loss of VE-cadherin and inflammatory lung injury. Notably, the administration of Syk inhibitor R788 (fostamatinib); currently in phase II clinical trial for the treatment of COVID-19, mitigated lung injury and mortality in mice with sepsis. These data identify Syk as a novel kinase for VE-cadherin and a druggable target against ALI in sepsis.","journal":"Journal of Biological Chemistry","year":2023,"id":348632,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1091856,"name":"Spencer Slavin","orcid":null,"position":1,"is_corresponding":false},{"id":1091857,"name":"Zahra Mahamed","orcid":null,"position":2,"is_corresponding":false},{"id":845603,"name":"Michelle Warren Millar","orcid":"0000-0001-6018-1307","position":3,"is_corresponding":false},{"id":1002349,"name":"Rauf Ahmad Najar","orcid":"0000-0003-2445-494X","position":4,"is_corresponding":false},{"id":1091858,"name":"Antony Leonard","orcid":null,"position":5,"is_corresponding":false},{"id":466771,"name":"Anthony P. Pietropaoli","orcid":null,"position":6,"is_corresponding":false},{"id":399633,"name":"David A. Dean","orcid":"0000-0001-7748-8073","position":7,"is_corresponding":false},{"id":846873,"name":"Fabeha Fazal","orcid":null,"position":8,"is_corresponding":false},{"id":845604,"name":"Arshad Rahman","orcid":"0000-0002-5621-0512","position":9,"is_corresponding":false},{"id":1002348,"name":"Mohammad Shadab","orcid":"0000-0003-4148-0365","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T01:12:10.335697Z","pmid":"38229397","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":[]}