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Peer-reviewedCC BYThe Journal of cell biology

The AMPK kinase Sak1 activates separase and promotes its nuclear localization during mitosis.

  • David Vaquero-Pelaz1
  • José-Antonio Rodriguez-Rodriguez1,2
  • Malina Carmina Ilinca1
  • Esther Casas-Fernández1
  • Amparo Picard1
  • Francisco Del Caño-Ochoa3,4
  • Isabel Vernia1
  • Toni Gabaldón5,6,7,8
  • Maria Angeles Juanes9,10
  • Ethel Queralt1
10 affiliations
  1. 1Instituto de Biomedicina de Valencia (IBV-CSIC) , Valencia, Spain.
  2. 2Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
  3. 3Structure of Macromolecular Targets Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain.
  4. 4Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), Associated Unit to the Instituto de Biomedicina de Valencia (IBV) , Valencia, Spain.
  5. 5Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
  6. 6Mechanisms of Disease Program, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology , Barcelona, Spain.
  7. 7ICREA, Pg. Lluis Companys 23 , Barcelona, Spain.
  8. 8Centro de Investigación Biomédica En Red de Enfermedades Infecciosas , Barcelona, Spain.
  9. 9National Horizons Centre, Teesside University , Darlington, UK.
  10. 10Centro de Investigacion Principe Felipe , Valencia, Spain.
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Abstract

Accurate chromosome segregation during mitosis requires the precise regulation of separase, a protease that cleaves cohesin to trigger the separation of sister chromatids. 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 pds1Δ 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.

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Cite

BibTeXRIS
BibTeX
@article{vaqueropelaz2026ampk,
  title = {{The AMPK kinase Sak1 activates separase and promotes its nuclear localization during mitosis.}},
  author = {David Vaquero-Pelaz and José-Antonio Rodriguez-Rodriguez and Malina Carmina Ilinca and Esther Casas-Fernández and Amparo Picard and Francisco Del Caño-Ochoa and Isabel Vernia and Toni Gabaldón and Maria Angeles Juanes and Ethel Queralt},
  journal = {The Journal of cell biology},
  year = {2026},
  month = oct,
  doi = {10.1083/jcb.202505056},
  url = {https://europepmc.org/article/MED/42900164},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The AMPK kinase Sak1 activates separase and promotes its nuclear localization during mitosis.
AU  - David Vaquero-Pelaz
AU  - José-Antonio Rodriguez-Rodriguez
AU  - Malina Carmina Ilinca
AU  - Esther Casas-Fernández
AU  - Amparo Picard
AU  - Francisco Del Caño-Ochoa
AU  - Isabel Vernia
AU  - Toni Gabaldón
AU  - Maria Angeles Juanes
AU  - Ethel Queralt
PY  - 2026
DA  - 2026/10/20
JO  - The Journal of cell biology
DO  - 10.1083/jcb.202505056
UR  - https://europepmc.org/article/MED/42900164
AB  - Accurate chromosome segregation during mitosis requires the precise regulation of separase, a protease that cleaves cohesin to trigger the separation of sister chromatids. 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 pds1Δ 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.
SN  - 0021-9525
SN  - 1540-8140
ER  -