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

•Mnk2 splice isoform acts like a tumor suppressor and is lost in cancer•Mnk2-splicing isoforms modulate the p38-MAPK stress pathway•The Mnk2a isoform suppresses transformation in vitro and in vivo•Mnk2a interacts with, phosphorylates, and translocates p38-MAPK into the nucleus

SummaryThe 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.

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