TY - JOUR
T1 - Mnk2 Alternative Splicing Modulates the p38-MAPK Pathway and Impacts Ras-Induced Transformation
AU - Maimon, Avraham
AU - Mogilevsky, Maxim
AU - Shilo, Asaf
AU - Golan-Gerstl, Regina
AU - Obiedat, Akram
AU - Ben-Hur, Vered
AU - Lebenthal-Loinger, Ilana
AU - Stein, Ilan
AU - Reich, Reuven
AU - Beenstock, Jonah
AU - Zehorai, Eldar
AU - Andersen, Claus L.
AU - Thorsen, Kasper
AU - Omtoft, Torben F.
AU - Davis, Roger J.
AU - Davidson, Ben
AU - Mu, David
AU - Karni, Rotem
AU - Ørntoft, Torben F.
N1 - US-Israel Bi-national Science Foundation [2009026]; Israeli Science Foundation [780/08, 1290/12]The authors wish to thank Prof. Rony Seger for the GFP-p38 alpha construct and comments on the manuscript; Prof. David Engelberg for the constitutively active p38 alpha 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.).
PY - 2014/4/24
Y1 - 2014/4/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899619503&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.celrep.2014.03.041
DO - https://doi.org/10.1016/j.celrep.2014.03.041
M3 - مقالة
C2 - 24726367
SN - 2211-1247
VL - 7
SP - 501
EP - 513
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -