{"doi":"10.1101/2022.10.07.511364","title":"The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation","abstract":"Summary cGMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an anti-tumor immune response. Recent studies reveal cGAS is frequently inhibited in cancer, and therapeutic targets to promote anti-tumor cGAS function remain elusive. c-Src is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that c-Src expression in tumors from various cancers negatively correlates with innate immune gene expression and patient survival. We determine that c-Src restricts cGAS signaling in human cell lines through c-Src small molecule inhibitors, depletion, and overexpression. cGAS and c-Src interact in cells and in vitro , while c-Src directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. c-Src phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces c-Src inhibition. Collectively, our study demonstrates that cGAS anti-tumor signaling is hindered by the proto-oncogene c-Src and describes how cancer-associated proteins can regulate the innate immune system.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":312220,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"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":331578,"name":"Shivam A. Zaver","orcid":"0000-0001-5254-0963","position":1,"is_corresponding":false},{"id":1010149,"name":"Cameron J. Howard","orcid":null,"position":2,"is_corresponding":false},{"id":331579,"name":"Joshua J. Woodward","orcid":"0000-0002-4630-403X","position":3,"is_corresponding":false},{"id":459454,"name":"William Dunker","orcid":"0000-0002-3271-4345","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T00:33:36.072096Z","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":[]}