{"doi":"10.1002/rth2.12710","title":"Clustering extent‐dependent differential signaling by CLEC‐2 receptors in platelets","abstract":"Background: C-type lectin receptor family members play a role in many cells including platelets, where they are crucial in the separation of lymphatic and blood vessels during development. The C-type lectin-like receptor 2 (CLEC-2) receptor contains the canonical intracellular hemITAM motif through which it signals to activate Syk. Objectives: One proposed hypothesis for signaling cascade is that Syk bridges two receptors through phosphorylated hemITAM motifs. We demonstrated that the phosphorylated hemITAM stimulates PI3 kinase/Btk pathways to activate Syk. To address this controversy, we used a CLEC-2 selective agonist and studied the role of Btk in platelet activation. Results and Conclusions: Platelet activation and downstream signaling were abolished in murine and human platelets in the presence of the Btk inhibitors ibrutinib or acalabrutinib when a low concentration of a CLEC-2 antibody was used to crosslink CLEC-2 receptors. This inhibition was overcome by increasing concentrations of the CLEC-2 antibody. Similar results were obtained in X-linked immunodeficient mouse platelets, with an inactivating mutation in Btk or in Lyn null platelets. We conclude that at low crosslinking conditions of CLEC-2, Btk plays an important role in the activation of Syk, but at higher crosslinking conditions their role becomes less important and other mechanisms take over to activate Syk.","journal":"Research and Practice in Thrombosis and Haemostasis","year":2022,"id":273932,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9667,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":915865,"name":"Hymavathi Reddy Vari","orcid":null,"position":1,"is_corresponding":false},{"id":915866,"name":"Monica Wright","orcid":null,"position":2,"is_corresponding":false},{"id":794369,"name":"John C. Kostyak","orcid":"0000-0002-8712-1192","position":3,"is_corresponding":false},{"id":516493,"name":"Satya P. Kunapuli","orcid":"0000-0002-1298-3214","position":4,"is_corresponding":false},{"id":516492,"name":"Carol Dangelmaier","orcid":"0000-0001-8941-7002","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T00:28:07.776043Z","pmid":"35573643","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":[]}