Disease relevance of MKNK1

• Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells [1].
• In vivo, 100k protein displaces Mnk1 from eIF4G during adenovirus infection, or in transfected cells [2].
• These data, combined with the clinical and cellular phenotype in Menkes disease, provide strong evidence that the MNK protein is involved in transmembrane copper efflux, and demonstrate a new system of gene amplification in mammalian cells [3].
• The dominantly inherited French type sialuria seems to result from defective allosteric feedback inhibitory regulation of GNE/MNK by cytidine monophosphate-N-acetylneuraminic acid (CMP-NANA), resulting in overproduction of cytosolic N-acetylneuraminic acid, and massive urinary excretion of free sialic acid [4].

High impact information on MKNK1

• A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNFalpha production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNFalpha 3'UTR [5].
• Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1 [6].
• Adenovirus is shown to prevent cellular translation by displacing Mnk1 from eIF4F, thereby blocking phosphorylation of eIF4E [2].
• Further, MNK1 was activated upon stimulation of HeLa cells with 12-O-tetradecanoylphorbol-13-acetate, fetal calf serum, anisomycin, UV irradiation, tumor necrosis factor-alpha, interleukin-1beta, or osmotic shock, and the activation by these stimuli was differentially inhibited by the MEK inhibitor PD098059 or the p38 MAP kinase inhibitor SB202190 [7].
• Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 [8].

Biological context of MKNK1

• The activity of eIF4E is thought to be regulated by interaction with inhibitory binding proteins (4E-BPs) and phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress [9].
• By using CGP 57380, a novel low-molecular-weight kinase inhibitor of MNK1, we demonstrate that eIF4E phosphorylation is not crucial to the formation of the initiation complex, mitogen-stimulated increase in cap-dependent translation, and cell proliferation [9].
• The C-terminal end in Mnk1 corresponds to the extracellular signal-regulated kinase (ERK1/2) binding site [10].
• Human Mnk1b mRNA is homologous to human Mnk1 mRNA but lacking a region corresponding to exon 19, which causes a change in the reading frame generating a stop codon [10].
• Here we identify a CRM1-type nuclear export motif in the C-terminal part of Mnk1 [11].

Anatomical context of MKNK1

• In line with these findings, addition of recombinant active MNK1 to rabbit reticulocyte lysate resulted in a reduced protein synthesis in vitro, and overexpression of MNK2 caused a decreased rate of protein synthesis in 293 cells [9].
• Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells [12].
• Immunohistochemistry of primary AML bone marrow biopsies showed strong cytoplasmic MNK1 expression in 25 of 99 AML specimens (25%) [13].
• Protein half-life analyses showed that PML-RARalpha enhanced MNK1 protein stability in U937 cells and ATRA exposure decreased MNK1 half-life in NB4 cells [13].
• Here, we report that Pi controls cell growth by activating ERK cascades and by facilitating the translocation of Mnk1 from cytosol into nucleus through an Akt-mediated MEK pathway [14].

Associations of MKNK1 with chemical compounds

• Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases [15].
• Expression of a dominant negative form of MNK1 in HEK293 cells leads to significant inhibition of cPLA2-mediated arachidonate release [15].
• Mutation of these serine residues to alanine or inhibition of Mnk1 activity increases the rate of ligand-induced degradation of hSpry2 [16].
• Treatment of HSC with 5 mM leucine did not alter half-life or steady state levels of procollagen alpha1(I) mRNA, but caused an increase in procollagen alpha1(I) protein that correlated with changes of components involved in translational regulation, like enhanced 4E-BP1, Mnk-1, and eIF4E phosphorylation [17].
• In addition, the phosphorylation of the eIF4E kinase, MAP kinase integrating kinase-1 (Mnk1), which is activated in response to growth factors or stress, was insensitive to SB203580 in DR-SAPK2a-expressing cells [18].

Physical interactions of MKNK1

• We propose a model whereby, in addition to its role in eIF4F assembly, eIF4G provides a docking site for Mnk1 to phosphorylate eIF4E [19].
• Here we identify mitogen-activated protein kinase-interacting kinase 1 (Mnk1) as the kinase that phosphorylates human Spry2 (hSpry2) on serines 112 and 121 [16].
• We conclude that Mnk1 activity stabilizes c-jun mRNA in polysomes independent of eIF4E phosphorylation [20].

Enzymatic interactions of MKNK1

• Over expression of an eIF4E mutant that cannot be phosphorylated by Mnk1 impairs translation of cellular but not viral late mRNAs [2].

Regulatory relationships of MKNK1

• The MAPK inhibitors or Mnk1 inhibitor blocked soluble interleukin (IL)-1beta and IL-8 production or release by 73-96% [21].

Other interactions of MKNK1

• Here we report that Mnk1 is associated with the eIF4F complex via its interaction with the C-terminal region of eIF4G [19].
• Furthermore, MNK1 and PRAK1, but not MSK1, is present in platelets and undergo modest activation in response to thrombin [15].
• The resistance exercise bout caused an increase in phosphorylation of the ERK 1/2, p90RSK and Mnk 1 proteins (P < 0.05) in the YM [22].
• Conversely, enhancement of serine phosphorylation achieved through either the inhibition of cellular phosphatases or the expression of active Mnk1 results in the stabilization of hSpry2 [16].
• A more detailed biological analysis in yeast showed that the Mnk2 interaction was selective for ERbeta as opposed to ERalpha and that the interaction was specific to Mnk2b as opposed to Mnk2a or Mnk1 [23].

Analytical, diagnostic and therapeutic context of MKNK1

• By Southern blot and FISH analysis we determined that the molecular basis for overexpression of MNK was genomic amplification of the MNK gene [3].
• The MNK gene codes for a P-type cation transporting ATPase, based on homology to known P-type ATPases and in vitro experimentation. cDNA clones of MNK in Menkes patients show diminished or absented hybridization in northern blot experiments [24].

References