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

Avraham Maimon; Maxim Mogilevsky; Asaf Shilo; Regina Golan-Gerstl; Akram Obiedat; Vered Ben-Hur; Ilana Lebenthal-Loinger; Ilan Stein; Reuven Reich; Jonah Beenstock; Eldar Zehorai; Claus L. Andersen; Kasper Thorsen; Torben F. Ørntoft; Roger J. Davis; Ben Davidson; David Mu; Rotem Karni

doi:10.1016/j.celrep.2014.03.041

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

Avraham Maimon, Maxim Mogilevsky, Asaf Shilo, Regina Golan-Gerstl, Akram Obiedat, Vered Ben-Hur, Ilana Lebenthal-Loinger, Ilan Stein, Reuven Reich, Jonah Beenstock, Eldar Zehorai, Claus L. Andersen, Kasper Thorsen, Torben F. Ørntoft, Roger J. Davis, Ben Davidson, David Mu, Rotem Karni^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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.

Original language	English
Pages (from-to)	501-513
Number of pages	13
Journal	Cell Reports
Volume	7
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2014.03.041
State	Published - 24 Apr 2014

Bibliographical note

Funding 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.).

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Maimon, A., Mogilevsky, M., Shilo, A., Golan-Gerstl, R., Obiedat, A., Ben-Hur, V., Lebenthal-Loinger, I., Stein, I., Reich, R., Beenstock, J., Zehorai, E., Andersen, C. L., Thorsen, K., Ørntoft, T. F., Davis, R. J., Davidson, B., Mu, D., & Karni, R. (2014). Mnk2 Alternative Splicing Modulates the p38-MAPK Pathway and Impacts Ras-Induced Transformation. Cell Reports, 7(2), 501-513. https://doi.org/10.1016/j.celrep.2014.03.041

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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.",

author = "Avraham Maimon and Maxim Mogilevsky and Asaf Shilo and Regina Golan-Gerstl and Akram Obiedat and Vered Ben-Hur and Ilana Lebenthal-Loinger and Ilan Stein and Reuven Reich and Jonah Beenstock and Eldar Zehorai and Andersen, {Claus L.} and Kasper Thorsen and {\O}rntoft, {Torben F.} and Davis, {Roger J.} and Ben Davidson and David Mu and Rotem Karni",

note = "Funding 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.). ",

year = "2014",

month = apr,

day = "24",

doi = "10.1016/j.celrep.2014.03.041",

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Maimon, A, Mogilevsky, M, Shilo, A, Golan-Gerstl, R, Obiedat, A, Ben-Hur, V, Lebenthal-Loinger, I, Stein, I, Reich, R, Beenstock, J, Zehorai, E, Andersen, CL, Thorsen, K, Ørntoft, TF, Davis, RJ, Davidson, B, Mu, D & Karni, R 2014, 'Mnk2 Alternative Splicing Modulates the p38-MAPK Pathway and Impacts Ras-Induced Transformation', Cell Reports, vol. 7, no. 2, pp. 501-513. https://doi.org/10.1016/j.celrep.2014.03.041

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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 - Ørntoft, Torben F.

AU - Davis, Roger J.

AU - Davidson, Ben

AU - Mu, David

AU - Karni, Rotem

N1 - Funding 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.).

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 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.

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 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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ER -

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

Abstract

Bibliographical note

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