Disease relevance of MAP2K2

• Mitogen-activated protein kinase kinase 2 (MEK2) was detected as an invasion-metastasis related factor between highly invasive (PC-1.0) and weakly invasive (PC-1) pancreatic cancer cell lines in our previous study [1].
• PURPOSE: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2 , in patients with advanced malignancy [2].
• These results suggest that mutations in the MEK-1 and MEK-2 gene occur at a very low frequency in human lung cancer [3].
• These results suggest that both MKK2 and PI4K230 are factors of a signal transduction pathway that might play an important role related to invasion and metastasis through the induction of cell motility and/or the inhibition of apoptosis [4].

High impact information on MAP2K2

• The results indicate that the phosphorylation of these two keratins is independently controlled by cyclic AMP-dependent kinase for MEK-2 and by cyclic nucleotide-independent kinase for MEK-1 [5].
• V8 protease digests revealed that phosphorylation of MEK-2 is restricted to one peptide representing approximately half the molecule [5].
• The phosphorylation of MEK-2 increased in the presence of 10(-4) M dibutyryl cyclic AMP (twofold), 1 mM methylisobutylxanthine (2.5-fold), 10(-5) M isoproterenol (fivefold), and 10(-9) M cholera toxin (sevenfold) [5].
• The ME-180 keratin proteins consist of two major subunits designated MEK-1 and MEK-2 with approximate molecular weights of 58,000 and 53,000, respectively, and six minor subunits of 59, 57, 52.5, 50.5, 45, and 40 kilodaltons [5].
• In this study, we show that YopJ exerts its deleterious effects by catalyzing the acetylation of two serine residues in the activation loop of the MAP kinase kinase, MEK2 [6].

Biological context of MAP2K2

• The MEK2 gene (MAP2K2) was mapped to chromosome 7q32 by fluorescence in situ hybridization and YAC clone analysis [7].
• Among these mRNAs, the MKK-2 mRNA encodes the protein kinase activator of ERK1/2 kinase, which is involved in the phosphorylation of eukaryotic initiation factor (eIF) 4E [8].
• As a result, mRNA translation may be regulated by the cellular level of MKK-2 [8].
• PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC50 value (50 microM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1 [9].
• CI-1040 (PD184352) is an orally active, highly specific, small-molecule inhibitor of one of the key components of this pathway (MEK1/MEK2), and thereby effectively blocks the phosphorylation of ERK and continued signal transduction through this pathway [10].

Anatomical context of MAP2K2

• Chemotactic peptide-induced activation of MEK-2, the predominant isoform in human neutrophils. Inhibition by wortmannin [11].
• Like MEK-1, MEK-2 was found to reside in the cytosol both before and after stimulation [11].
• Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells [12].
• Introduction of Ras dominant-negative (D/N) and MEK2 D/N genes into ChangX-34 cells significantly alleviated centrosome amplification, whereas introduction of the PKC D/N and PKB D/N genes did not [13].
• However, U0126 (a MEK1/2 inhibitor) treatment apparently induced the plasma membrane distribution of claudin-1 and aggregation of single cells in PC-1.0 and AsPC-1 cells, synchronously seriously suppressed MEK2 and p-MEK1/2 expression [14].

Associations of MAP2K2 with chemical compounds

• MAPKK1 and MAPKK2 have apparent molecular masses of 45 kDa and 47 kDa, respectively, on SDS/polyacrylamide gel electrophoresis [15].
• 5. In contrast, UO126 was highly effective at inhibiting IL-1beta-dependent arachidonate release, implicating MEK2 in the activation of the PLA(2) that is involved in IL-1beta-dependent PGE(2) release [16].
• 6. We conclude that the MEK1, MEK2 and p38 MAP kinase inhibitors, PD098059, UO126 and SB203580, are highly potent in respect of inflammatory PG release [16].
• METHODS: Human ASM cells were cultured in 96-well plates with or without cerivastatin in the presence or absence of mitogen-activated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase MEK1/MEK 2 inhibitor PD98059 [17].
• When ME-180 cells were incubated for 2-24 h in the presence of [32P]orthophosphate, MEK-1 and MEK-2 as well as the 52.5- and 40-kilodalton keratins were phosphorylated at their serine residues [5].

Enzymatic interactions of MAP2K2

• MEK1 and MEK2 phosphorylate a majority of the ERK2 mutants [18].

Regulatory relationships of MAP2K2

• In our previous investigations, mitogen-activated protein kinase kinase 2 (MEK2)/extracellular signal-regulated kinase 2 (ERK2) signaling pathway was found to be correlated with the cell dissociation induced by dissociation factor (DF) in pancreatic cancer cells [19].
• In addition, neither Mek1 nor Mek2 are stably activated in coordination with Raf-1 in nocodazole-arrested cells [20].

Other interactions of MAP2K2

• In particular, MEK-2 was considerably more sensitive than MEK-1 to the phosphatidylinositol 3-kinase inhibitor wortmannin [11].
• Preincubation of human neutrophils with 50 microM PD098059 almost completely (>90%) inhibited the FMLP-induced activation of MEK-1 and MEK-2, the isoforms expressed by neutrophils [21].
• In addition, these docking-site peptides inhibited MEK2-ERK2 binding [22].
• Basic fibroblast growth factor induces the expression of matrix metalloproteinase-3 in human periodontal ligament cells through the MEK2 mitogen-activated protein kinase pathway [23].
• ERK5 did not interact with MEK1 or MEK2 [24].

Analytical, diagnostic and therapeutic context of MAP2K2

• In this study, immunocytochemistry and Western blot analysis were performed in pancreatic cancer cells using anti-claudin-1, MEK2 and phosphorylated MEK1/2 (p-MEK1/2) antibodies to reveal the correlation between TJ and cancer cell dissociation, as well as the involvement of MEK2 in regulation of TJ in cell dissociation of pancreatic cancer [14].
• Thus the 35 kDa protein was isolated by immunoprecipitation with the phospho-MKK1/MKK2 antibody and identified by MS [25].
• Two competitive enzyme immunoassays using digoxigenin-labeled peptides have been developed for the quantification of the protein kinase MEK2 in cell extracts [26].
• The specific expressions of MKK2 and PI4K230 in the highly invasive and metastatic cell line PC-1.0 were confirmed by RT-PCR and Northern blotting [4].

References