MAPK family signaling cascades

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser
Click the image above or here to open this pathway in the Pathway Browser
The mitogen activated protein kinases (MAPKs) are a family of conserved protein serine threonine kinases that respond to varied extracellular stimuli to activate intracellular processes including gene expression, metabolism, proliferation, differentiation and apoptosis, among others.
The classic MAPK cascades, including the ERK1/2 pathway, the p38 MAPK pathway, the JNK pathway and the ERK5 pathway are characterized by three tiers of sequentially acting, activating kinases (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011). The MAPK kinase kinase kinase (MAPKKK), at the top of the cascade, is phosphorylated on serine and threonine residues in response to external stimuli; this phosphorylation often occurs in the context of an interaction between the MAPKKK protein and a member of the RAS/RHO family of small GTP-binding proteins. Activated MAPKKK proteins in turn phosphorylate the dual-specificity MAPK kinase proteins (MAPKK), which ultimately phosphorylate the MAPK proteins in a conserved Thr-X-Tyr motif in the activation loop.
Less is known about the activation of the atypical families of MAPKs, which include the ERK3/4 signaling cascade, the ERK7 cascade and the NLK cascade. Although the details are not fully worked out, these MAPK proteins don't appear to be phosphorylated downstream of a 3-tiered kinase system as described above (reviewed in Coulombe and Meloche, 2007; Cargnello and Roux, 2011) .
Both conventional and atypical MAPKs are proline-directed serine threonine kinases and, once activated, phosphorylate substrates in the consensus P-X-S/T-P site. Both cytosolic and nuclear targets of MAPK proteins have been identified and upon stimulation, a proportion of the phosphorylated MAPKs relocalize from the cytoplasm to the nucleus. In some cases, nuclear translocation may be accompanied by dimerization, although the relationship between these two events is not fully elaborated (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011; Plotnikov et al, 2010).
Literature References
PubMed ID Title Journal Year
17161475 Atypical mitogen-activated protein kinases: structure, regulation and functions

Meloche, S, Coulombe, P

Biochim. Biophys. Acta 2007
22535895 Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update

Kyriakis, JM, Avruch, J

Physiol. Rev. 2012
21167873 The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation

Zehorai, E, Procaccia, S, Seger, R, Plotnikov, A

Biochim. Biophys. Acta 2011
21372320 Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases

Roux, PP, Cargnello, M

Microbiol. Mol. Biol. Rev. 2011
Orthologous Events
Cite Us!