Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling
Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling
Eukaryotic elongation factor 2 kinase (eEF2K), an atypical calmodulin-dependent protein kinase, phosphorylates and inhibits eEF2, slowing down translation elongation. eEF2K contains an N-terminal catalytic domain, a C-terminal ?-helical region and a linker containing several regulatory phosphorylation sites. eEF2K is expressed at high levels in certain cancers, where it may act to help cell survival, e.g., during nutrient starvation. However, it is a negative regulator of protein synthesis and thus cell growth, suggesting that cancer cells may possess mechanisms to inhibit eEF2K under good growth conditions, to allow protein synthesis to proceed. We show here that the mTORC1 pathway and the oncogenic Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway cooperate to restrict eEF2K activity. We identify multiple sites in eEF2K whose phosphorylation is regulated by mTORC1 and/or ERK, including new ones in the linker region. We demonstrate that certain sites are phosphorylated directly by mTOR or ERK. Our data reveal that glycogen synthase kinase 3 signaling also regulates eEF2 phosphorylation. In addition, we show that phosphorylation sites remote from the N-terminal calmodulin-binding motif regulate the phosphorylation of N-terminal sites that control CaM binding. Mutations in the former sites, which occur in cancer cells, cause the activation of eEF2K. eEF2K is thus regulated by a network of oncogenic signaling pathways.
4088-4103
Wang, X.
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Regufe da Mota, S.
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Liu, R.
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Moore, C. E.
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Xie, J.
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Lanucara, F.
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Agarwala, U.
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Pyr dit Ruys, S.
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Vertommen, D.
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Rider, M.H.
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Eyers, C.E.
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Proud, C. G.
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November 2014
Wang, X.
976221d1-3004-409c-8640-715bedfc5d15
Regufe da Mota, S.
fe39404b-e413-4834-97c6-0f2204b500a9
Liu, R.
8fa8346c-3a65-4f80-be37-18f8c620e4a3
Moore, C. E.
25775426-fa7e-445d-a861-9fff65c19c4f
Xie, J.
7193521d-61a0-4f8d-a836-d10be096f399
Lanucara, F.
67909ff8-b229-4e63-822d-60b240387938
Agarwala, U.
ba3a8591-c163-4259-b1cf-20a700d2d1d6
Pyr dit Ruys, S.
e32ed26b-bf57-49d9-b3fe-d3af315f988c
Vertommen, D.
6bd40dd5-644e-4a80-9bff-26d58b0f3082
Rider, M.H.
048fd0e0-8d39-4f40-8053-af812236253e
Eyers, C.E.
38d97c2c-06d6-4bf8-99a1-89187b518404
Proud, C. G.
4b924871-4b30-48d4-aa5b-9234be7c650b
Wang, X., Regufe da Mota, S., Liu, R., Moore, C. E., Xie, J., Lanucara, F., Agarwala, U., Pyr dit Ruys, S., Vertommen, D., Rider, M.H., Eyers, C.E. and Proud, C. G.
(2014)
Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling.
Molecular and Cellular Biology, 34 (22), .
(doi:10.1128/MCB.01035-14).
(PMID:25182533)
Abstract
Eukaryotic elongation factor 2 kinase (eEF2K), an atypical calmodulin-dependent protein kinase, phosphorylates and inhibits eEF2, slowing down translation elongation. eEF2K contains an N-terminal catalytic domain, a C-terminal ?-helical region and a linker containing several regulatory phosphorylation sites. eEF2K is expressed at high levels in certain cancers, where it may act to help cell survival, e.g., during nutrient starvation. However, it is a negative regulator of protein synthesis and thus cell growth, suggesting that cancer cells may possess mechanisms to inhibit eEF2K under good growth conditions, to allow protein synthesis to proceed. We show here that the mTORC1 pathway and the oncogenic Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway cooperate to restrict eEF2K activity. We identify multiple sites in eEF2K whose phosphorylation is regulated by mTORC1 and/or ERK, including new ones in the linker region. We demonstrate that certain sites are phosphorylated directly by mTOR or ERK. Our data reveal that glycogen synthase kinase 3 signaling also regulates eEF2 phosphorylation. In addition, we show that phosphorylation sites remote from the N-terminal calmodulin-binding motif regulate the phosphorylation of N-terminal sites that control CaM binding. Mutations in the former sites, which occur in cancer cells, cause the activation of eEF2K. eEF2K is thus regulated by a network of oncogenic signaling pathways.
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Accepted/In Press date: 14 August 2014
e-pub ahead of print date: 2 September 2014
Published date: November 2014
Organisations:
Molecular and Cellular
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Local EPrints ID: 384630
URI: http://eprints.soton.ac.uk/id/eprint/384630
ISSN: 0270-7306
PURE UUID: db1dac70-bbc3-4fc0-acbc-ed0d4694a339
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Date deposited: 03 Dec 2015 16:12
Last modified: 14 Mar 2024 22:01
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Contributors
Author:
X. Wang
Author:
S. Regufe da Mota
Author:
R. Liu
Author:
C. E. Moore
Author:
J. Xie
Author:
F. Lanucara
Author:
U. Agarwala
Author:
S. Pyr dit Ruys
Author:
D. Vertommen
Author:
M.H. Rider
Author:
C.E. Eyers
Author:
C. G. Proud
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