Disease relevance of MAPK6

• Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines [1].
• The human ERK3 gene was mapped by fluorescence in situ hybridization to chromosome 15q21, a region associated with chromosomal abnormalities in acute nonlymphoblastic leukemias [2].
• The alterations in the non-coding region of ERK3 gene cloned from oral cancer tissue, may affect stability or regulation of mRNA, resulting in overexpression in the patient samples [3].

High impact information on MAPK6

• N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome [4].
• Importantly, we identified a fusion peptide between the N-terminal methionine of ERK3 and the C-terminal glycine of ubiquitin in vivo by tandem mass spectrometry analysis [4].
• These findings demonstrate that ERK3 is conjugated to ubiquitin via its free NH(2) terminus [4].
• To explore the molecular diversity of the ERK-3 subfamily, we isolated a novel human cDNA, designated Hu-ERK-3, from a fetal skeletal muscle library [5].
• Finally, cell cycle synchronization studies revealed that the subcellular localization of ERK3 is temporally regulated [6].

Biological context of MAPK6

• In humans, database analysis has revealed the presence of six MAPK6 processed pseudogenes localized on four different chromosomes [7].
• In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin [8].
• ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus [8].
• Our results suggest that nucleocytoplasmic shuttling of ERK3 is required for its negative regulatory effect on cell cycle progression [9].
• Immunoblotting with antibodies raised to recombinant protein and to peptides from the catalytic core and three regions of the C-terminal tail revealed that ERK3 is the expected size and is ubiquitously expressed in a variety of cell lines and tissues [10].

Anatomical context of MAPK6

• In the present study, expression of p97MAPK was unique among the ERK family in that its expression was induced when human carcinoma cell lines are plated on type IV collagen [1].
• Although expression of p97MAPK was detected in all of the tissues tested by Northern (RNA) analysis, the most abundant expression was seen in skeletal muscle [5].
• Importantly, we show that enforced localization of ERK3 in the nucleus or cytoplasm markedly attenuates the ability of the kinase to induce cell cycle arrest in fibroblasts [9].
• In contrast, ERK3 was restricted to the distal lung epithelium during the pseudoglandular phase (E17) but shifted to the proximal airways, particularly Clara cells during the saccular stage (E21) [11].
• Overexpression of ERK-3 was correlated to TNM staging (average ratio of integral optic density (IOD)(tumor): IOD(normal) in TNM I, II, III, IV tumors was 1.43+/-0.34, 5.08+/-3.74, 4.99+/-1.08, 1.44+/-1.02, n = 42, P = 0.023) and serosa invasion (4.31+/-4.34 vs 2.00+/-2.03, P = 0.037) [12].

Associations of MAPK6 with chemical compounds

• Treatment of cells with leptomycin B causes the nuclear accumulation of ERK3 in a high percentage of cells [9].
• Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase family of serine/threonine kinases [9].

Other interactions of MAPK6

• We further show that the structure of MAPK6 is closely related to that of the gene encoding the homologous protein kinase p63(MAPK) (MAPK4), suggesting that the two genes arose by duplication [7].
• Regulation of ERK3/MAPK6 expression by BRAF [13].
• Identification of extracellular signal-regulated kinase 3 as a new interaction partner of cyclin D3 [14].

Analytical, diagnostic and therapeutic context of MAPK6

• Northern blot analysis revealed that ERK3 mRNA is widely distributed in human tissues, with the highest expression detected in skeletal muscle [2].
• Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma [3].
• Confocal microscopy examining the subcellular localization of ERK3 in several cell lines indicated that this enzyme was targeted to the Golgi/endoplasmic reticulum Golgi intermediate compartment [6].
• The binding of cyclin D3 and ERK3 was further confirmed in vivo by co-immunoprecipitation assay and confocal microscopic analysis [14].

References