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.

Naro, C., Barbagallo, F., Chieffi, P., Bourgeois, C., Paronetto, M., Sette, C. (2014). The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival. NUCLEIC ACIDS RESEARCH, 42(5), 3218-3227 [10.1093/nar/gkt1307].

The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival

SETTE, CLAUDIO
2014-03-01

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.
mar-2014
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/16 - ANATOMIA UMANA
English
Con Impact Factor ISI
Neoplasms; Apoptosis; Nuclear Proteins; Alternative Splicing; RNA-Binding Proteins; Humans; Cell Line, Tumor; Cell Nucleus; Protein-Serine-Threonine Kinases; bcl-X Protein; Cell Survival
www.ncbi.nlm.nih.gov/pubmed/24369428
Naro, C., Barbagallo, F., Chieffi, P., Bourgeois, C., Paronetto, M., Sette, C. (2014). The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival. NUCLEIC ACIDS RESEARCH, 42(5), 3218-3227 [10.1093/nar/gkt1307].
Naro, C; Barbagallo, F; Chieffi, P; Bourgeois, C; Paronetto, M; Sette, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/101232
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