{"doi":"10.1016/j.jbc.2023.104774","title":"Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression","abstract":"Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.","journal":"Journal of Biological Chemistry","year":2023,"id":353806,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"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":291277,"name":"Irene Bertolini","orcid":"0000-0001-5824-6802","position":1,"is_corresponding":false},{"id":291276,"name":"Ekta Agarwal","orcid":"0000-0002-5992-3358","position":2,"is_corresponding":false},{"id":291279,"name":"Jagadish C. Ghosh","orcid":"0000-0002-1832-4578","position":3,"is_corresponding":false},{"id":258003,"name":"Hsin‐Yao Tang","orcid":"0000-0003-1838-018X","position":4,"is_corresponding":false},{"id":258005,"name":"David W. Speicher","orcid":"0000-0003-1311-4261","position":5,"is_corresponding":false},{"id":626660,"name":"Frederick Keeney","orcid":null,"position":6,"is_corresponding":false},{"id":363777,"name":"Khalid Sossey‐Alaoui","orcid":"0000-0002-2410-7633","position":7,"is_corresponding":false},{"id":783958,"name":"Elżbieta Pluskota","orcid":"0000-0003-2924-3842","position":8,"is_corresponding":false},{"id":225496,"name":"Katarzyna Białkowska","orcid":"0000-0001-8489-6665","position":9,"is_corresponding":false},{"id":325911,"name":"Edward F. Plow","orcid":"0000-0003-1531-9746","position":10,"is_corresponding":false},{"id":291280,"name":"Lucia R. Languino","orcid":"0000-0001-9011-7031","position":11,"is_corresponding":false},{"id":420812,"name":"Emmanuel Skordalakes","orcid":"0000-0002-7600-2833","position":12,"is_corresponding":false},{"id":258002,"name":"M. Cecilia Caino","orcid":"0000-0001-8294-8070","position":13,"is_corresponding":false},{"id":291281,"name":"Dario C. Altieri","orcid":"0000-0002-0617-3469","position":14,"is_corresponding":false},{"id":1100490,"name":"Minjeong Yeon","orcid":"0000-0003-4784-2240","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:13:02.680107Z","pmid":"37142218","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":[]}