{"doi":"10.1101/2025.10.09.681531","title":"Optogenetic control of PLC-γ1 activity directs cell motility","abstract":"ABSTRACT Phospholipase C-γ1 (PLC-γ1) signaling is required for mesenchymal chemotaxis, but is it sufficient to bias motility? PLC-γ1 enzyme activity is basally autoinhibited, and light-controlled membrane recruitment of wild-type PLC-γ1 (OptoPLC-γ1) in Plcg1- null fibroblasts does not trigger lipid hydrolysis, complicating efforts to isolate its contribution. Utilizing cancer-associated mutations to investigate the regulatory logic of PLC-γ1, we demonstrate that a hallmark of enzyme activity, phosphorylated Tyr783 (pTyr783), is not a proxy for activity level, but is rather a marker of dysregulated autoinhibition. Accordingly, OptoPLC-γ1 with a deregulating mutation (P867R, S345F, or D1165H) exhibits elevated phosphorylation, and membrane localization of such is sufficient to activate substrate hydrolysis and concomitant motility responses. In particular, local recruitment of OptoPLC-γ1 S345F polarizes cell motility and migration on demand. This response is spatially dose-sensitive and only partially reduced by blocking canonical PLC-γ1 signaling yet is lipase-dependent. Our findings reframe the interpretation of PLC-γ1 regulation and demonstrate that local activation of PLC-γ1 is sufficient to direct cell motility.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577616,"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":0.9537,"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":18209,"name":"Priscila F. Siesser","orcid":null,"position":1,"is_corresponding":false},{"id":1394405,"name":"Harrison H. Truscott","orcid":null,"position":2,"is_corresponding":false},{"id":546798,"name":"Nicole Hajicek","orcid":"0000-0001-7457-4830","position":3,"is_corresponding":false},{"id":30214,"name":"John Sondek","orcid":"0000-0002-1127-8310","position":4,"is_corresponding":false},{"id":453521,"name":"James E. Bear","orcid":"0000-0002-8489-996X","position":5,"is_corresponding":false},{"id":453522,"name":"Jason M. Haugh","orcid":"0000-0002-2476-4027","position":6,"is_corresponding":false},{"id":1141146,"name":"Ravikanth Appalabhotla","orcid":null,"position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:58:16.148027Z","pmid":"41280018","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":[]}