Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells.

Autor: Recasens A; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. ariadna.recasens@sydney.edu.au., Humphrey SJ; Charles Perkins Centre and School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia., Ellis M; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Hoque M; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Abbassi RH; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Chen B; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Longworth M; School of Chemistry, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia., Needham EJ; Charles Perkins Centre and School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia., James DE; Charles Perkins Centre and School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia., Johns TG; Oncogenic Signalling Laboratory, Telethon Kids Institute, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA, 6009, Australia., Day BW; QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia., Kassiou M; School of Chemistry, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia., Yang P; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.; Charles Perkins Centre and School of Mathematics and Statistics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia.; Computational Systems Biology Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW, 2145, Australia., Munoz L; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. lenka.munoz@sydney.edu.au.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2021 Apr 16; Vol. 7 (1), pp. 81. Date of Electronic Publication: 2021 Apr 16.
DOI: 10.1038/s41420-021-00456-6
Abstrakt: Both tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.
Databáze: MEDLINE
Externí odkaz: