The Erk5 MAPK signaling pathway, also known as the big MAP kinase responds to various stresses and under certain conditions to growth factors. Erk5 displays the characteristic three-tier core cascade MAPK architecture. The only downstream and effector in the MAPK tier is Erk5 (represented by Mapk7); its activation requires phosphorylation of threonine and tyrosine residues within the conserved TEY motif in the activation loop by dual specificity kinase of the middle MAP2K tier (Mkk5 represented
by Map2k5) in turn activated by the two kinases of the MAP3K tier (Mekk2 and 3, represented by Map3k2 and Map3k3). Like all MAPKs, Mapk7 is a serine/threonine kinase whose substrates are primarily transcription factors. Erk5/Mapk7 has been reported to exhibit nuclear export and transcriptional activator activities both of which are localized to the C-terminal portion of the protein that also accounts for its more than twice the size of the other MAPKs. Adapters such as Sh2d2a (known as Lad or Ribp), upstream kinases such as Wnk1 or activators including members of the Ras family such as Rap1 have been reported; yet overall relatively little is known about how this pathway is regulated. Erk5 signaling appears to play important roles in proliferation and survival, particularly in the cardiovascular and neuronal systems. Deregulation of the pathway has been linked to cancer and tumorigenesis; the effect appears to be due to deregulation of pathways upstream of Erk5. Ras, which has been implicated in many types of human cancer has been shown to activate the Erk5 pathway in certain cell types. In addition, abnormal activity or expression of Mapk7 or Map2k5 has been observed in breast cancer cell and prostate cancer. To see
the ontology report for annotations, GViewer and download, click here[click to see related GO term – GO:0007254, KEGG map – map04010 and entry at Reactome - REACT_12020.1]...(less)
