MAPK6: Human MAP Kinase 6 (ERK3)
PDB Code: 2I6L
MAPK6 is an atypical member of the ERK family. Within this subfamily it is mostly similar to ERK1 and ERK2. However, MAPK6 has several unusual features: the phosphorylation motif in MAPK6 is S-E-G instead of the T-E-Y motif found in ERK1 and ERK2. As a consequence activation of MAPK6 does not require dual specificity phosphorylation activity since the activation segment tyrosine is mimicked by a glutamate residue. In addition S-P-R replaces the A-P-E motif, a highly conserved motif found C-terminal to the activation segment in most kinases. However, the precise function of MAPK6 has not been established yet but it is thought to be involved in regulation of cell cycle and inhibition of DNA synthesis as well as S-phase entry.
MAPK6 shuttles between nucleus and cytoplasm and this nucleo-cytoplasmic shuttling is necessary for its inhibitory effect on DNA synthesis. The MAPK6 protein is highly unstable due to two regions (NDR1 and NDR2) located in the N-terminal lobe that have been described to mediate proteasomal degradation. The half life of the protein is dependent on the differentiation state of the cell. MAPK6 can be phosphorylated by MEK2 on serine and threonine residues.
MAPK6 expression in the lung is restricted to the distal lung epithelium during the pseudoglandular phase (E17) but shifts to the proximal airways, particularly Clara cells during the saccular stage (E21). Enhanced MAPK6 activity has been described in fibroblasts and upon treatment with serum or phorbol esters.
MAPK6 is over-expressed in several human cancers including oral squamous cell carcinoma , colon cancer, gastric cancer and high expression levels have been associated with tumor progression

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