Disease relevance of MAP2K5

• We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue [1].
• We also investigated MEK5 expression in different breast carcinoma cell lines and breast cancer tissues using tissue array analysis [2].
• Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival [1].
• We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters [1].
• Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease [3].

High impact information on MAP2K5

• Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C [4].
• MEK5 is the only MAP2K to express a PB1 domain, and we have shown that it heterodimerizes with the PB1 domain of MEKK2 [5].
• They further show that the activating phosphorylation of ERK5 by MEK5 results in the dissociation of the binding between the N- and C-terminal halves and thus inhibits nuclear export of ERK5, causing its nuclear import [6].
• Here we demonstrate that the aPKCs interact in an EGF-inducible manner with MEK5 and that this interaction is required and sufficient for the activation of MEK5 in response to EGF [7].
• [Ru(CO)(3)Cl(2)](2) activated PPARdelta transcriptional activity via the MEK5/ERK5 signaling pathway [8].

Chemical compound and disease context of MAP2K5

• Therefore, we examined the endogenous expression status of MEK5 in androgen-independent prostate cancer cells upon recombinant adenovirus-mediated introduction of MBP-1 [9].

Biological context of MAP2K5

• MEK5 transfection experiments confirm its ability to induce proliferation (P < 0.0001), motility (P = 0.0001) and invasion in prostate cancer cells (P = 0.0001) [1].
• The upregulation of MEK5 by Stat3-C was further confirmed by Western blot in MCF10A breast epithelial cells [2].
• An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro [10].
• MKK5 expressed as a glutathione S-transferase fusion protein in human embryonic kidney 293 cells activated full-length extracellular-signal-regulated protein kinase (ERK)5 (ERK5wt) as well as the isolated catalytic domain (ERK5cat) in vitro [10].
• In this study, we have investigated whether inhibition of MEK5 signaling pathway can modulate prostate cancer cell growth [9].

Anatomical context of MAP2K5

• Much less information is available about the MEK5-ERK5 module and its role in renal epithelial cell proliferation and differentiation [11].
• Both MEK5 and ERK5 are expressed in many adult tissue and are abundant in heart and skeletal muscle [12].
• Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation [13].
• MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation [14].
• The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha [15].

Physical interactions of MAP2K5

• Through utilization of a yeast two-hybrid screen, we have identified MEKK3 as a molecule that physically interacts with MEK5 [16].

Regulatory relationships of MAP2K5

• ERK5 activation was blocked by the MEK5 inhibitor U0126 and expression of a dominant negative MEK5 mutant [17].
• Together, our results suggested a novel role of MBP-1 for suppression of prostate cancer cell growth by regulating the MEK5-mediated signaling pathway [9].

Other interactions of MAP2K5

• MEK5 is the upstream BMK1 kinase and exists as naturally occurring splice variants, MEK5alpha and MEK5beta [18].
• MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion [1].
• This interaction appears to take place in mammalian cells as evidenced by the fact that cellular MEK5 and MEKK3 co-immunoprecipitate [16].
• Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified [19].
• MEKK3 regulates MKK3 and MKK5/6/7 [20].

Analytical, diagnostic and therapeutic context of MAP2K5

• The MEK5 cDNA was isolated by degenerate PCR and encodes a 444-amino acid protein, which has approximately 40% identity to known MEKs [12].
• RT-PCR result also demonstrated that MEK5 mRNA was significantly induced by Stat3-C in TERT cells [2].
• RESULTS: Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells [21].

References