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Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties

Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties
Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties
The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E.
0021-9258
37623-37633
Parra, J.L.
f11649c3-e751-4c2c-b91b-a3567638098f
Buxade, M.
3929371b-f21d-4fb2-8d65-c8086ef44311
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e
Parra, J.L.
f11649c3-e751-4c2c-b91b-a3567638098f
Buxade, M.
3929371b-f21d-4fb2-8d65-c8086ef44311
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e

Parra, J.L., Buxade, M. and Proud, C.G. (2005) Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties. The Journal of Biological Chemistry, 280 (45), 37623-37633. (doi:10.1074/jbc.M508356200).

Record type: Article

Abstract

The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E.

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Published date: 1 November 2005

Identifiers

Local EPrints ID: 56121
URI: https://eprints.soton.ac.uk/id/eprint/56121
ISSN: 0021-9258
PURE UUID: 02f5dfd6-68af-4c8c-8342-e40360e49a69

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Date deposited: 07 Aug 2008
Last modified: 13 Mar 2019 20:35

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