Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

Philipp Trulley; Goda Snieckute; Dorte Bekker-Jensen; Manoj B Menon; Robert Freund; Alexey Kotlyarov; Jesper V Olsen; Manuel D Diaz-Muñoz; Martin Turner; Simon Bekker-Jensen; Matthias Gaestel; Christopher Tiedje

doi:10.1016/j.celrep.2019.05.024

Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

Philipp Trulley, Goda Snieckute, Dorte Bekker-Jensen, Manoj B Menon, Robert Freund, Alexey Kotlyarov, Jesper V Olsen, Manuel D Diaz-Muñoz, Martin Turner, Simon Bekker-Jensen, Matthias Gaestel, Christopher Tiedje

Molecular Aging Program

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Abstract

Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38^MAPK-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5′ UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties. In the present study, Trulley et al. identify a N-terminal extended long isoform of the stress-activated protein kinase MK2 that constitutively arises from alternative translation initiation within the known MK2 mRNA. The long isoform has unique and shared molecular properties, compared to the canonical short isoform.

Original language	English
Journal	Cell Reports
Volume	27
Issue number	10
Pages (from-to)	2859-2870.e6
Number of pages	19
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2019.05.024
Publication status	Published - 4 Jun 2019

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Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2Final published version, 3.4 MBLicence: CC BY

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Trulley, P., Snieckute, G., Bekker-Jensen, D., Menon, M. B., Freund, R., Kotlyarov, A., Olsen, J. V., Diaz-Muñoz, M. D., Turner, M., Bekker-Jensen, S., Gaestel, M., & Tiedje, C. (2019). Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2. Cell Reports, 27(10), 2859-2870.e6. https://doi.org/10.1016/j.celrep.2019.05.024

Trulley, P, Snieckute, G, Bekker-Jensen, D, Menon, MB, Freund, R, Kotlyarov, A, Olsen, JV, Diaz-Muñoz, MD, Turner, M, Bekker-Jensen, S, Gaestel, M & Tiedje, C 2019, 'Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2', Cell Reports, vol. 27, no. 10, pp. 2859-2870.e6. https://doi.org/10.1016/j.celrep.2019.05.024

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title = "Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2",

abstract = "Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38MAPK-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5′ UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties. In the present study, Trulley et al. identify a N-terminal extended long isoform of the stress-activated protein kinase MK2 that constitutively arises from alternative translation initiation within the known MK2 mRNA. The long isoform has unique and shared molecular properties, compared to the canonical short isoform.",

author = "Philipp Trulley and Goda Snieckute and Dorte Bekker-Jensen and Menon, {Manoj B} and Robert Freund and Alexey Kotlyarov and Olsen, {Jesper V} and Diaz-Mu{\~n}oz, {Manuel D} and Martin Turner and Simon Bekker-Jensen and Matthias Gaestel and Christopher Tiedje",

year = "2019",

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doi = "10.1016/j.celrep.2019.05.024",

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T1 - Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

AU - Trulley, Philipp

AU - Snieckute, Goda

AU - Bekker-Jensen, Dorte

AU - Menon, Manoj B

AU - Freund, Robert

AU - Kotlyarov, Alexey

AU - Olsen, Jesper V

AU - Diaz-Muñoz, Manuel D

AU - Turner, Martin

AU - Bekker-Jensen, Simon

AU - Gaestel, Matthias

AU - Tiedje, Christopher

PY - 2019/6/4

Y1 - 2019/6/4

N2 - Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38MAPK-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5′ UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties. In the present study, Trulley et al. identify a N-terminal extended long isoform of the stress-activated protein kinase MK2 that constitutively arises from alternative translation initiation within the known MK2 mRNA. The long isoform has unique and shared molecular properties, compared to the canonical short isoform.

AB - Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38MAPK-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5′ UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties. In the present study, Trulley et al. identify a N-terminal extended long isoform of the stress-activated protein kinase MK2 that constitutively arises from alternative translation initiation within the known MK2 mRNA. The long isoform has unique and shared molecular properties, compared to the canonical short isoform.

U2 - 10.1016/j.celrep.2019.05.024

DO - 10.1016/j.celrep.2019.05.024

M3 - Journal article

C2 - 31167133

SN - 2211-1247

VL - 27

SP - 2859-2870.e6

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

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