Mnk2 Alternative Splicing Modulates the p38-MAPK Pathway and Impacts Ras-Induced Transformation

Avraham Maimon, Maxim Mogilevsky, Asaf Shilo, Regina Golan-Gerstl, Akram Obiedat, Vered Ben-Hur, Ilana Lebenthal-Loinger, Ilan Stein, Reuven Reich, Jonah Beenstock, Eldar Zehorai, Claus L. Andersen, Kasper Thorsen, Torben F. Omtoft, Roger J. Davis, Ben Davidson, David Mu, Rotem Karni, Torben F. Ørntoft

Research output: Contribution to journalArticlepeer-review


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 down-regulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38 alpha-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 p38 alpha-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.
Original languageEnglish
Pages (from-to)501-513
Number of pages13
JournalCell Reports
Issue number2
StatePublished - 24 Apr 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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