The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity inmammalian cells
Gc. Scheper et al., The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity inmammalian cells, MOL CELL B, 21(3), 2001, pp. 743-754
The cap-binding translation initiation factor eukaryotic initiation factor
4E (eIF4E) is phosphorylated in vivo at Ser209 in response to a variety of
stimuli. In this paper, we show that the mitogen-activated protein kinase (
MAPK) signal-integrating kinase Mnk2 phosphorylates eIF4E at this residue.
Mnk2 binds to the scaffolding protein eIF4G, and overexpression of Mnk2 res
ults in increased phosphorylation of endogenous eIF4E, shelving that it can
act as an eIF4E kinase in vivo. We have identified eight phosphorylation s
ites in Mnk2, of which at least three potential MAPK sites are likely to be
essential for Mnk2 activity. In contrast to that of Mnk1, the activity of
overexpressed Mnk2 is high under control conditions and could only be reduc
ed substantially by a combination of PD98059 and SB203580, while the activi
ty of endogenous Mnk2 in Swiss 3T3 cells was hardly affected upon treatment
with these inhibitors. These compounds did not abolish phosphorylation of
eIF4E, implying that Mnk2 may mediate phosphorylation of eIF4E in Swiss 3T3
cells. In vitro phosphorylation studies show that Mnk2 is a significantly
better substrate than Mnk1 for extracellular signal-regulated kinase 2 (ERK
2), p38MAPK alpha, and p38MAPK beta. Therefore, the high levels of activity
of Mnk2 under several conditions may be explained by efficient activation
of Mnk2 by low levels of activity of the upstream kinases, Interestingly, w
e found that the association of both Mnk1 and Mnk2 with eIF4G increased upo
n inhibition of the MAPK pathways while activation of ERK resulted in decre
ased binding to eIF4G. This might reflect a mechanism to ensure rapid, but
transient, phosphorylation of eIF4E upon stimulation of the MAPK pathways.