Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation.
Cell Rep
; 7(2): 501-513, 2014 Apr 24.
Article
en En
| MEDLINE
| ID: mdl-24726367
ABSTRACT
The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Núcleo Celular
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Transformación Celular Neoplásica
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Proteínas Serina-Treonina Quinasas
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Empalme Alternativo
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Sistema de Señalización de MAP Quinasas
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Proteínas Quinasas p38 Activadas por Mitógenos
Límite:
Animals
Idioma:
En
Año:
2014
Tipo del documento:
Article