{"doi":"10.1101/2025.04.16.648985","title":"Steady-state phosphorylation of SHIP1 by Lyn restricts macrophage activation in the absence of a phagocytic synapse","abstract":"Abstract Microscale engagement of the hemi-ITAM-containing receptor Dectin-1 by a fungus-derived particle initiates signaling through the Src-family kinases (SFKs) and Syk that leads to downstream Erk and Akt activation and the macrophage anti-microbial response. To minimize local tissue damage in the absence of a true pathogenic threat, macrophages must remain unresponsive to low-valency receptor ligation by soluble ligands from food or remote infection sites. To investigate how SFKs regulate macrophage sensitivity, we compared signaling in murine bone-marrow-derived macrophages (BMDMs) exposed to depleted zymosan, a particulate and highly multivalent Dectin-1 ligand, with signaling after pharmacologically induced SFK activation without receptor engagement or formation of a phagocytic synapse. We show that high-valency Dectin-1 engagement and formation of a phagocytic synapse restrict phosphorylation of the ITIM-associated phosphatase SHIP1 and promote Erk and Akt signaling. In contrast, SFK activation in the absence of a phagocytic synapse induces phosphorylation of SHIP1 and leads to dampened activation of Erk and Akt. Whereas multiple SFKs are capable of phos-phorylating SHIP1 in principle, the SFK Lyn functions uniquely in maintaining steady-state phosphorylation of SHIP1 and setting tonic and induced levels of Erk and Akt phosphorylation. Consequently, Lyn has a special role in suppressing the Akt pathway and maintaining Erk/Akt pathway balance. Interestingly, formation of a phagocytic synapse circumvents this requirement for Lyn to maintain Erk/Akt balance. These findings highlight the unique function of Lyn in maintaining mac-rophage steady-state signaling and limiting pro-inflammatory responses to disorganized pathway activation and soluble microbial components.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557603,"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":0.9584,"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":569988,"name":"William K. Kanagy","orcid":"0000-0002-5756-9965","position":1,"is_corresponding":false},{"id":367818,"name":"Richard Cattley","orcid":null,"position":2,"is_corresponding":false},{"id":497590,"name":"Whitney Swanson","orcid":"0000-0002-6247-5920","position":3,"is_corresponding":false},{"id":1457449,"name":"Silvia Toledo Ramos","orcid":"0009-0009-5049-4145","position":4,"is_corresponding":false},{"id":574567,"name":"Myra G. Nunez","orcid":"0000-0002-6886-6287","position":5,"is_corresponding":false},{"id":237072,"name":"William F. Hawse","orcid":"0000-0001-8371-3345","position":6,"is_corresponding":false},{"id":644611,"name":"Tanya S. Freedman","orcid":"0000-0001-5168-5829","position":7,"is_corresponding":false},{"id":717098,"name":"S. Erandika Senevirathne","orcid":"0000-0001-9637-440X","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","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":[]}