{"doi":"10.1016/j.celrep.2023.112539","title":"PhosY-secretome profiling combined with kinase-substrate interaction screening defines active c-Src-driven extracellular signaling","abstract":"c-Src tyrosine kinase is a renowned key intracellular signaling molecule and a potential target for cancer therapy. Secreted c-Src is a recent observation, but how it contributes to extracellular phosphorylation remains elusive. Using a series of domain deletion mutants, we show that the N-proximal region of c-Src is essential for its secretion. The tissue inhibitor of metalloproteinases 2 (TIMP2) is an extracellular substrate of c-Src. Limited proteolysis-coupled mass spectrometry and mutagenesis studies verify that the Src homology 3 (SH3) domain of c-Src and the P 31 VHP 34 motif of TIMP2 are critical for their interaction. Comparative phosphoproteomic analyses identify an enrichment of PxxP motifs in phosY-containing secretomes from c-Src-expressing cells with cancer-promoting roles. Inhibition of extracellular c-Src using custom SH3-targeting antibodies disrupt kinase-substrate complexes and inhibit cancer cell proliferation. These findings point toward an intricate role for c-Src in generating phosphosecretomes, which will likely influence cell-cell communication, particularly in c-Src-overexpressing cancers.","journal":"Cell Reports","year":2023,"id":341127,"datarank":0.41588830833596724,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.0,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"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":873157,"name":"SarahBeth D. Votra","orcid":null,"position":1,"is_corresponding":false},{"id":261611,"name":"Matthew P. Stokes","orcid":null,"position":2,"is_corresponding":false},{"id":580394,"name":"Endre Sebestyén","orcid":"0000-0001-5470-2161","position":3,"is_corresponding":false},{"id":1038966,"name":"Matteo Castelli","orcid":"0000-0002-3673-0262","position":4,"is_corresponding":false},{"id":1076642,"name":"Luca Torielli","orcid":"0000-0001-7655-2037","position":5,"is_corresponding":false},{"id":347007,"name":"Giorgio Colombo","orcid":"0000-0002-1318-668X","position":6,"is_corresponding":false},{"id":346994,"name":"Mark R. Woodford","orcid":"0000-0002-6737-2832","position":7,"is_corresponding":false},{"id":347006,"name":"Mehdi Mollapour","orcid":"0000-0002-2144-1361","position":8,"is_corresponding":false},{"id":346998,"name":"Dimitra Bourboulia","orcid":"0000-0002-8567-2775","position":9,"is_corresponding":false},{"id":346995,"name":"Sarah J. Backe","orcid":"0000-0001-9275-267X","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:11:03.393978Z","pmid":"37243593","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":[]}