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Here, we identify the AMPK-activating kinase Sak1 as a novel regulator of separase in Saccharomyces cerevisiae. Using a suppressor screen, we discovered a hypermorphic SAK1-E50K allele that restored separase activity and nuclear localization in esp1-2 and pds1\u0394 mutants. We demonstrated that Sak1 phosphorylates separase independently of Snf1 activation, enhancing its enzymatic function and promoting nuclear accumulation. Loss of Sak1 delays Cdc14 activation and phenocopies FEAR pathway defects, establishing Sak1 as a mitotic regulator. Extending these findings to humans, we demonstrated that human separase and the tumor suppressor kinase LKB1, which is homologous to Sak1, physically associate. This finding reveals an evolutionarily conserved regulatory link between LKB1 and separase, highlighting the kinase-protease interplay as a critical mechanism for ensuring faithful mitotic progression.<\/jats:p>","DOI":"10.1083\/jcb.202505056","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:36:24Z","timestamp":1792503384000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["The AMPK kinase Sak1 activates separase and promotes its nuclear localization during mitosis"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9992-3619","authenticated-orcid":true,"given":"David","family":"Vaquero-Pelaz","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5263-0210","authenticated-orcid":true,"given":"Jos\u00e9-Antonio","family":"Rodriguez-Rodriguez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]},{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center 2 , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8105-1499","authenticated-orcid":true,"given":"Malina Carmina","family":"Ilinca","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4652-4818","authenticated-orcid":true,"given":"Esther","family":"Casas-Fern\u00e1ndez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-5444","authenticated-orcid":true,"given":"Amparo","family":"Picard","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3093-3103","authenticated-orcid":true,"given":"Francisco","family":"Del Ca\u00f1o-Ochoa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gfc7t72","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV), CSIC 3 Structure of Macromolecular Targets Unit, , Valencia,","place":["Spain"]},{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Valencia Biomedical Research Foundation, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe (CIPF), Associated Unit to the Instituto de Biomedicina de Valencia (IBV) 4 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8244-6767","authenticated-orcid":true,"given":"Isabel","family":"Vernia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05pq8vh42","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Biomedicina de Valencia (IBV-CSIC) 1 , Valencia,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-1735","authenticated-orcid":true,"given":"Toni","family":"Gabald\u00f3n","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05sd8tv96","id-type":"ROR","asserted-by":"publisher"}],"name":"Barcelona Supercomputing Center (BSC) 5 Life Sciences Department, , Barcelona,","place":["Spain"]},{"name":"Mechanisms of Disease Program, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology 6 , Barcelona,","place":["Spain"]},{"name":"ICREA, Pg. 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