{"doi":"10.1101/2025.06.30.662394","title":"Latrophilin-2 Orchestrates Endothelial Flow-Mediated Smad1/5 Activation via Endoglin and Shank3","abstract":"Abstract Fluid shear stress (FSS) from blood flow critically determines vascular morphology and function. FSS activates the Smad1/5 pathway maximally at physiological FSS through the BMP9/10 receptors Alk1 and Endoglin to promote vascular stability. We now report that the adhesion G protein-coupled receptor Latrophilin-2 (Lphn2), which mediates flow activation of the canonical junctional complex, is required for flow-mediated Smad1/5 activation in endothelial cells. Lphn2 physically associates with Endoglin and is required for Smad1/5 activation by FSS but not soluble BMP9. This regulation is independent of G-proteins but requires Lphn2’s C-terminal PDZ binding motif. Endothelial-specific Lphn2 knockout reduces Smad1/5 activation in mice. In zebrafish embryos, loss of flow or Lphn2 knockout similarly reduced endothelial Smad1/5 activation, with no additive effect, indicating that Lphn2 mediates flow-induced activation in vivo . APEX2 proximity labeling revealed that the PDZ domain-containing scaffold protein Shank3 associated with Lphn2 under flow. Shank3 knockdown blocked flow-induced Smad1/5 activation in vitro and Shank3 global knockout mice exhibited reduced endothelial nuclear Smad1/5 and increased susceptibility to arteriovenous malformations. Lphn2 thus mediates flow-induced Smad1/5 activation and vessel stabilization through the scaffold protein Shank3, independently of G proteins. Together with the accompanying paper on Notch1, we conclude that Lphn2 confers FSS sensitivity to three of the major FSS pathways via distinct mechanisms.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558397,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"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":1169848,"name":"Manasa Chanduri","orcid":"0000-0002-9353-1438","position":1,"is_corresponding":false},{"id":671958,"name":"Minghao Chen","orcid":"0000-0001-7719-3961","position":2,"is_corresponding":false},{"id":329359,"name":"Andrew Prendergast","orcid":"0000-0001-5985-325X","position":4,"is_corresponding":false},{"id":270346,"name":"Martin A. Schwartz","orcid":"0000-0002-2071-1243","position":5,"is_corresponding":false},{"id":260725,"name":"Anne Eichmann","orcid":"0000-0001-5563-210X","position":6,"is_corresponding":false},{"id":560953,"name":"Keiichiro Tanaka","orcid":"0000-0001-6328-1485","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40631150","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":[]}