UMMS Affiliation

Program in Molecular Medicine

Date

4-24-2014

Document Type

Article

Medical Subject Headings

Active Transport, Cell Nucleus; *Alternative Splicing; Animals; Cell Nucleus; Cell Transformation, Neoplastic; *MAP Kinase Signaling System; Mice; Protein Binding; Protein-Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases; ras Proteins

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

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 p38alpha-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 p38alpha-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.

Rights and Permissions

Citation: Cell Rep. 2014 Apr 24;7(2):501-13. doi: 10.1016/j.celrep.2014.03.041. Epub 2014 Apr 13. Link to article on publisher's site

Comments

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Related Resources

Link to Article in PubMed

PubMed ID

24726367

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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