title: Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Maimon
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Maxim
authors.initials: M
authors.lastname: Mogilevsky
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Shilo
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Regina
authors.initials: R
authors.lastname: Golan-Gerstl
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Akram
authors.initials: A
authors.lastname: Obiedat
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Ben-Hur
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Lebenthal-Loinger
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Stein
authors.affiliation: Department of Pharmacology, Institute for Drug Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.affiliation: Department of Biological Chemistry, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Jonah
authors.initials: J
authors.lastname: Beenstock
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eldar
authors.initials: E
authors.lastname: Zehorai
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Skejby, 8200 Aarhus N, Denmark.
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Skejby, 8200 Aarhus N, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Thorsen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Skejby, 8200 Aarhus N, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: 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.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Mu
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: rotemka@ekmd.huji.ac.il.
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
mesh_terms: D021581:Active Transport, Cell Nucleus; D017398:Alternative Splicing; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C106282:Mknk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins