title: Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1/human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.
abstract: PTTG1, also known as securin, is an inactivating partner of separase, the major effector for chromosome segregation during mitosis. At the metaphase-to-anaphase transition, securin is targeted for proteasomal destruction by the anaphase-promoting complex or cyclosome, allowing activation of separase. In addition, securin is overexpressed in metastatic or genomically instable tumors, suggesting a relevant role for securin in tumor progression. Stability of securin is regulated by phosphorylation; some phosphorylated forms are degraded out of mitosis, by the action of the SKP1-CUL1-F-box protein (SCF) complex. The kinases targeting securin for proteolysis have not been identified, and mechanistic insight into the cause of securin accumulation in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. Importantly, a strong correlation between securin accumulation and GSK3β inactivation was observed in breast cancer tissues, indicating that GSK3β inactivation may account for securin accumulation in breast cancers.
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mora-Santos
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Limón-Mortés
authors.forename: Servando
authors.initials: S
authors.lastname: Giráldez
authors.forename: Joaquín
authors.initials: J
authors.lastname: Herrero-Ruiz
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
authors.forename: Miguel Á
authors.initials: MÁ
authors.lastname: Japón
authors.forename: Maria
authors.initials: M
authors.lastname: Tortolero
authors.forename: Francisco
authors.initials: F
authors.lastname: Romero
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D064249:Securin
chemical_list: D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D044843:SKP Cullin F-Box Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3