title: The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival.
abstract: NEK2 is a serine/threonine kinase that promotes centrosome splitting and ensures correct chromosome segregation during the G2/M phase of the cell cycle, through phosphorylation of specific substrates. Aberrant expression and activity of NEK2 in cancer cells lead to dysregulation of the centrosome cycle and aneuploidy. Thus, a tight regulation of NEK2 function is needed during cell cycle progression. In this study, we found that NEK2 localizes in the nucleus of cancer cells derived from several tissues. In particular, NEK2 co-localizes in splicing speckles with SRSF1 and SRSF2. Moreover, NEK2 interacts with several splicing factors and phosphorylates some of them, including the oncogenic SRSF1 protein. Overexpression of NEK2 induces phosphorylation of endogenous SR proteins and affects the splicing activity of SRSF1 toward reporter minigenes and endogenous targets, independently of SRPK1. Conversely, knockdown of NEK2, like that of SRSF1, induces expression of pro-apoptotic variants from SRSF1-target genes and sensitizes cells to apoptosis. Our results identify NEK2 as a novel splicing factor kinase and suggest that part of its oncogenic activity may be ascribed to its ability to modulate alternative splicing, a key step in gene expression regulation that is frequently altered in cancer cells.
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy, Laboratories of Neuroembryology and of Cellular and Molecular Neurobiology, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy, Department of Psychology, II University of Naples, Caserta, Italy, Department of Functional Genomics and Cancer, Institut de Genetique et de Biologie Moleculaire et Cellulaire, F-67400, INSERM U964, F-67400 Illkirch, France and Department of Health Sciences, University of Rome Foro Italico, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Naro
authors.forename: Federica
authors.initials: F
authors.lastname: Barbagallo
authors.forename: Paolo
authors.initials: P
authors.lastname: Chieffi
authors.forename: Cyril F
authors.initials: CF
authors.lastname: Bourgeois
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Paronetto
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival; D006801:Humans; D000072379:NIMA-Related Kinases; D009369:Neoplasms / Q000201:enzymology*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051020:bcl-X Protein; D000068103:Serine-Arginine Splicing Factors; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases