{"doi":"10.15252/msb.202211127","title":"A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells","abstract":"Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to \"secrete-and-sense\" growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαβγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control, allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose-response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint GFs (e.g., the epidermal GF) as key stimuli for such self-sustenance. Findings highlight how the enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors.","journal":"Molecular Systems Biology","year":2023,"id":357134,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"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":807708,"name":"Saptarshi Sinha","orcid":"0000-0002-4100-5727","position":1,"is_corresponding":false},{"id":348400,"name":"Amer Ali Abd El‐Hafeez","orcid":"0000-0002-4822-6581","position":2,"is_corresponding":false},{"id":530183,"name":"I‐Chung Lo","orcid":"0000-0002-2632-3436","position":3,"is_corresponding":false},{"id":476006,"name":"Krishna Midde","orcid":null,"position":4,"is_corresponding":false},{"id":354097,"name":"Tony Ngo","orcid":"0000-0002-6779-2546","position":5,"is_corresponding":false},{"id":474900,"name":"Nicolas Aznar","orcid":"0000-0003-3338-9932","position":6,"is_corresponding":false},{"id":383996,"name":"Inmaculada López-Sánchez","orcid":null,"position":7,"is_corresponding":false},{"id":818008,"name":"Vijay Gupta","orcid":"0000-0002-3613-6378","position":8,"is_corresponding":false},{"id":818667,"name":"Marilyn G. Farquhar","orcid":null,"position":9,"is_corresponding":false},{"id":232970,"name":"Padmini Rangamani","orcid":"0000-0001-5953-4347","position":10,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":11,"is_corresponding":false},{"id":818007,"name":"Lingxia Qiao","orcid":"0000-0003-2639-6851","position":0,"is_corresponding":true}],"reference_count":128,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:13:34.795336Z","pmid":"36856068","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":[]}