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.
Bibliographical noteFunding Information:
The authors wish to thank Prof. Rony Seger for the GFP-p38α construct and comments on the manuscript; Prof. David Engelberg for the constitutively active p38α mutant and other p38-MAPK proteins and fruitful discussions; Prof. Eli Pikarsky for his help in tumor pathological analysis; Prof. Oded Meyuhas, Dr. Zahava Kluger, and Dr. Ittai Ben Porath for comments on the manuscript; members of the Engelberg and Ben Porath labs for sharing reagents and discussions; and members of the R.K. lab for helpful discussions. This work was supported by the US-Israel Bi-national Science Foundation (grant no. 2009026) and Israeli Science Foundation (grant nos. 780/08 and 1290/12) (to R.K.).