ual specificity kinases of the middle MAP2K tier (here Mek represented by Map2k1 and 2), in turn activated by the upstream MAP3K tier (here Raf). While the Raf proteins are the main MAP3Ks, other MAP3Ks can activate this and other MAPK signaling (e.g. Map3k1/Mekk1 also acting as a MAP3K for JNK pathway). Downstream of growth factors activated receptor tyrosine kinases, various effectors and adapters lead to activation of small monomeric G proteins of the Ras family. Activated Ras bind to and recruit the Raf proteins to the plasma membrane where through a series of phosphorylation, dephosphorylation and other events they get activated. Of the several members of Ras, Kras appears to be a more potent inducer of the Raf/Mek/Erk cascade. The three mammalian Raf proteins - Araf, Braf and Raf1/Craf are serine/threonine kinases whose primary targets are the Map2k1/Mek1 and Map2k2/Mek2 members of the MAP2K tier. Mapk1/Erk2 and Mapk3/Erk1 are serine/threonine kinases whose targets include transcription factors, cytoplasmic proteins as well as other kinases referred to as MAPKAPK. The latter can be considered a fourth tier which further transmits the signal through the many targets it controls. Phosphorylated MAPKs are the targets of many phosphatases such as Pp2a - a serine/threonine phosphatase complex, Ptprr (known as PTP-SL) - a tyrosine phosphatase, or by members of the dual specificity phosphatases of the MKP/Dusp family, eg. Dusp6. Pp2a dephosphorylates and downregulates the activity of Mek while dephosphorylation of Raf helps rescue it from an inactive state leading to its activation. Pp2a activity is stimulated by kinases and appears to be a target of p38 MAPK raising the possibility that Erk signaling is negatively regulated by p38 MAPK pathway. Raf is negatively regulated by phosphorylation within the regulatory domain, eg. Akt, or through the interaction with Pebp1/Rkip that inhibits its kinase activity. Scaffold proteins, such as Ksr1 and KSR2 (human, help organize the core modules and shape their activity. Ksr1 and KSR2 form ternary complexes with Raf and Mek and display kinase activity towards Mek (not shown). The scaffolding and catalytic attributes promote and/ or facilitate Raf activity towards Mek. The MAPKs can also provide feedback regulatory loops to the upstream components of the pathway. Raf/Mek/Erk pathway regulates processes such as proliferation, differentiation. Deregulation of the pathway either through mutations in the core or upstream components (eg B-Raf, Ras) or other pathways that regulate it (eg PI3K/Akt) has been implicated in human cancer. To see the ontology report for annotations, GViewer and download, click here
[click to see related GO term - GO:0070371, KEGG map - map04010 and entries at Reactome - REACT_962.4;     REACT_1482.4]...(less)