Disease relevance of Map2k2

• These results indicate that MK2 plays a key role in regulation of smalpha expression, and that targeting MK2 might present a therapeutic approach in managing conditions such as pulmonary fibrosis [1].
• Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented [2].
• In summary, these data show that gene deletion of MK2 ameliorates cerulein-induced pancreatitis [3].
• We investigated the possible negative regulation of the cell cycle by protein kinase C (PKC) isoforms in synchronously grown BALB/MK-2 mouse keratinocytes, in which PKC isoforms were overexpressed by using the adenovirus vector Ax [4].

High impact information on Map2k2

• However, despite the sustained loss of full-length mitogen-activated protein kinase kinase 2, by 48 h, TIR macrophages regained diphosphorylated extracellular response kinases 1,2, suggesting an adaptation led to recovery of this signaling pathway [5].
• Altogether, our findings demonstrate that MEK2 is not necessary for the normal development of the embryo and T-cell lineages, suggesting that the loss of MEK2 can be compensated for by MEK1 [6].
• Mek2 is dispensable for mouse growth and development [6].
• Although several components of the ERK/MAP kinase cascade have been implicated in thymocyte development, no such involvement was observed for MEK2, which appears to be nonessential for thymocyte differentiation and T-cell-receptor-induced proliferation and apoptosis [6].
• In detached cells placed in suspension, ERK2 was complexed with MEK2 but not with MEK1 [7].

Biological context of Map2k2

• These findings suggest that MEK2 is a member of a multigene family [8].
• MEK1 and MEK2 are shown to be encoded by different genes and are located on murine chromosomes 9 and 10, respectively [8].
• The MEK2 protein bears substantial sequence homology to MEK1, except at its amino terminus, and at a proline-rich region insert between the conserved kinase subdomains 9 and 10 [8].
• The human MEK1 shares 99% amino acid sequence identity with the murine MEK1 and 80% with human MEK2 [9].
• However, the proline-rich MK2 N terminus provides a distinct role restricted to cell migration [10].

Anatomical context of Map2k2

• By contrast, there was no evidence of MEK2 activation in macrophages in response to TNF alpha [11].
• The MAPKs and MEK2 are expressed in all premeiotic germ cells and spermatocytes, while MEK1 is not expressed abundantly in pachytene spermatocytes [12].
• In addition, migration of MK2-deficient mouse embryonic fibroblasts (MEFs) and smooth muscle cells on fibronectin is dramatically reduced [10].
• We further show that, in MK2-deficient macrophages, formation of filopodia in response to extracellular stimuli is reduced [10].
• Cell-migration assays indicated that mek1-/- fibroblasts could not be induced to migrate by fibronectin, although the levels of Mek2 protein and Erk activation were normal [13].

Associations of Map2k2 with chemical compounds

• Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not [8].
• Using a murine knockout model, we have previously shown that elimination of MK2 leads to a dramatic reduction of tumor necrosis factor (TNF) production in response to lipopolysaccharide [10].
• In addition, a specific MEK1/MEK2 inhibitor, PD98059 (60 microM), reduced the GnRH and PMA responses whereas the L-type voltage-gated calcium channel agonist, +/- BayK 8644 (5 microM), and antagonist, nimodipine (250 nM), had no effect on GnRH responsiveness [14].
• Neurite outgrowth, increased expression of growth-associated protein 43, and decreased incorporation of bromodeoxyuridine (BrdU) were induced by treatment with GDNF, H-RasV12, or a constitutively active MEK2 [15].
• Surprisingly, MEK2 but not MEK1 was the principal mediator of estradiol-induced activation of ERK [16].

Physical interactions of Map2k2

• We show that MK2 stabilizes p38 MAPK through its C terminus and that MK2 catalytic activity does not contribute to this stabilization [10].

Regulatory relationships of Map2k2

• Time-lapsed video microscopy and confocal imaging were used to study the migration of wild-type (WT) and mitogen-activated protein kinase-activated protein kinase 2 (MK2-/-) mouse neutrophils in Zigmond chambers containing fMLP gradients [17].

Other interactions of Map2k2

• Taken together, our findings indicate that Fyn-calcineurin-NFATc2 and MEK2-ERK1/2 are two independent signaling pathways that cooperate to control T cell receptor-mediated ICOS induction [18].
• Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-alpha by NGF [19].
• As a result of activation MK2 is exported from the nucleus to the cytoplasm and cotransports active p38 MAPK to this compartment [10].
• These data indicate that catalytic activity of MK2 is required for both cytokine production and cell migration [10].
• Confocal images of polarized WT neutrophils showed an intracellular gradient of phospho-MK2 from the anterior to the posterior region of the neutrophils [17].

Analytical, diagnostic and therapeutic context of Map2k2

• Western blot analyses of MEK1 and MEK2 in 14.5-day-old embryonic and adult mouse tissue confirm the RNA analysis [20].
• PS/2, R1-2, or MK2 significantly inhibited the recruitment of eosinophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid and decreased inflammation in the lung tissues [21].

References