{"doi":"10.26508/lsa.202503599","title":"The Notch1 intracellular domain orchestrates mechanotransduction of fluid shear stress","abstract":"<jats:p>Hemodynamic shear stress regulates endothelial phenotype through activation of Notch1 signaling, yet the mechanistic basis for this activation is unclear. Here, we establish a fluid shear stress–dependent mechanism of Notch1 activation that is distinct from canonical ligand trans-endocytosis. Application of unidirectional laminar flow triggers the rapid spatial polarization of full-length Notch1 heterodimers into downstream membrane microdomains. Unlike canonical transactivation, Notch1 receptors are cis-endocytosed into the receptor-bearing cell within polarized microdomains. We discover that the Notch1 intracellular domain critically orchestrates receptor polarization and proteolytic cleavage in response to flow, but is dispensable for canonical ligand transactivation. Shear stress increases intracellular domain interaction with annexin A2 and caveolar proteins, which control Notch1 cis-endocytosis and proteolytic activation. These findings define a flow-specific Notch1 mechanotransduction mechanism linking receptor polarization and endocytosis with proteolytic activation and illuminate a new pathway by which mechanical forces integrate with Notch receptor activation.</jats:p>","journal":"Life Science Alliance","year":2026,"id":656872,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":751108,"name":"Kyle A. 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Application of unidirectional laminar flow triggers the rapid spatial polarization of full-length Notch1 heterodimers into downstream membrane microdomains. Unlike canonical transactivation, Notch1 receptors are cis-endocytosed into the receptor-bearing cell within polarized microdomains. We discover that the Notch1 intracellular domain critically orchestrates receptor polarization and proteolytic cleavage in response to flow, but is dispensable for canonical ligand transactivation. Shear stress increases intracellular domain interaction with annexin A2 and caveolar proteins, which control Notch1 cis-endocytosis and proteolytic activation. These findings define a flow-specific Notch1 mechanotransduction mechanism linking receptor polarization and endocytosis with proteolytic activation and illuminate a new pathway by which mechanical forces integrate with Notch receptor activation.</jats:p>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41644301","pmcid":"PMC12877406","openalex_id":"https://openalex.org/W7128024950","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"GM150987, AG072232, GM142944, S10OD028611","title":null},{"funder_name":"Leducq Foundation","grant_id":"21CVD03","title":null},{"funder_name":"NIH Predoctoral Fellowship","grant_id":"HL162520","title":null},{"funder_name":"TRDRP Predoctoral Fellowship","grant_id":"T33DT6442","title":null},{"funder_name":"NSF GRFP","grant_id":"2038436","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R21 AG072232","title":null},{"funder_name":"NIH HHS","grant_id":"S10 OD028611","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"F31 HL162520","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R35 GM150987","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R35 GM142944","title":null}],"total_grants":10,"fwci":14.1335,"citation_percentile":0.98836148,"influential_citations":0,"citation_trend":[{"year":2026,"count":4}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.26508/lsa.202503599","host_type":"journal"},{"url":"https://doi.org/10.26508/lsa.202503599","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.26508/lsa.202503599","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41644301","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12877406","host_type":"repository"},{"url":"https://doaj.org/article/b5be80748fbb49229f4e1fb1982c291a","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12877406/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12877406","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12877406?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Developmental Biology and Gene Regulation","Axon Guidance and Neuronal Signaling","Barrier Structure and Function Studies","Receptor, Notch1","Mechanotransduction, Cellular","Stress, Mechanical","Humans","Endocytosis","Signal Transduction","Animals","Protein Domains","Annexin A2","Membrane Microdomains","Proteolysis"],"mesh_terms":["Protein Domains","Animals","Endocytosis","Humans","Stress, Mechanical","Signal Transduction","Annexin A2","Membrane Microdomains","Mechanotransduction, Cellular","Endothelial Cells","Receptor, Notch1","Proteolysis"],"keywords":["Mechanotransduction","Intracellular","Endocytosis","Receptor","Internalization","Shear stress","G protein-coupled receptor","Notch signaling pathway"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T22:39:49.125454Z","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":[]}