Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation

Cell Rep. 2014 Apr 24;7(2):501-513. doi: 10.1016/j.celrep.2014.03.041.

Avraham Maimon ¹, Maxim Mogilevsky ¹, Asaf Shilo ¹, Regina Golan-Gerstl ¹, Akram Obiedat ¹, Vered Ben-Hur ¹, Ilana Lebenthal-Loinger ¹, Ilan Stein ², Reuven Reich ³, Jonah Beenstock ⁴, Eldar Zehorai ⁵, Claus L Andersen ⁶, Kasper Thorsen ⁶, Torben F Ørntoft ⁶, Roger J Davis ⁷, Ben Davidson ⁸, David Mu ⁹, Rotem Karni ¹⁰

Affiliations

1 Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
2 Department of Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
3 Department of Pharmacology, Institute for Drug Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
4 Department of Biological Chemistry, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
5 Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
6 Department of Molecular Medicine, Aarhus University Hospital, Skejby, 8200 Aarhus N, Denmark.
7 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
8 Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Ullernchausseen 70, Oslo 0310, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo 0424, Norway.
9 Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, 651 Colley Avenue, Norfolk, VA 23501, USA.
10 Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: [email protected].

PMID: 24726367 DOI: 10.1016/j.celrep.2014.03.041

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 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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