Program in Molecular Medicine
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
Biochemistry | Cell Biology | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes | Genetic Phenomena | Investigative Techniques | Molecular Biology | Neoplasms | Skin and Connective Tissue Diseases
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.
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DOI of Published Version
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
Maimon A, Mogilevsky M, Shilo A, Golan-Gerstl R, Obiedat A, Ben-Hur V, Lebenthal-Loinger I, Stein I, Reich R, Beenstock J, Zehorai E, Andersen CL, Thorsen K, Orntoft TF, Davis RJ, Davidson B, Mu D, Karni R. (2014). Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation. Davis Lab Publications. https://doi.org/10.1016/j.celrep.2014.03.041. Retrieved from https://escholarship.umassmed.edu/davis/49
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