MAPK Signaling
Phosphorylation is the reversible process of attaching a phosphate group to a specific amino-acid residue on a protein. Functionally, phosphorylation acts as a simple molecular switch that can activate, deactivate, or modulate the function of a protein. Addition and removal of phosphate groups provide spatial and temporal control over protein activity. Phosphorylation is tightly controlled by a competing interdependent network of kinases - which donate phosphate groups to a substrate protein, and phosphorylases - which remove them from a substrate.
Mitogen-activated protein kinases (MAPKs) are a highly conserved and ubiquitously expressed family of enzymatic kinases that phosphorylate many different target substrates. MAP-kinases are part of a larger, tiered phosphorylation cascade that includes MAP2Ks and MAP3Ks. This tiered organization affords flexibility, allowing a broad range of higher-order kinases to respond to stimuli and control cellular function through activation of a smaller subset of MAP-kinases that interact directly with other functional proteins.
MAP-kinases play a major role in nearly every cellular process. MAPK dependent phosphorylation is implicated in signaling cascades that regulate cell-cycle progression, differentiation, development, and apoptosis. Dysregulation of this pathway is implicated in numerous diseases. MAPK signaling plays a central role in the development and progression of various cancers due to its influence on cell proliferation and survival. Aberrant MAPK activation can lead to excessive immune responses and inflammation. In Rheumatoid arthritis (RA), overactivation of MAPK pathways contributes to synovial inflammation and joint damage, whereas in Psoriasis it promotes keratinocyte proliferation and inflammation. MAPK signaling is also involved in neuronal stress responses and apoptosis, linking it to conditions like: Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). In AD excessive MAPK activation (e.g., p38 MAPK) is associated with tau phosphorylation and neuroinflammation. In PD and ALS dysregulation of MAPK signaling contributes to neuronal death.
Related Pathways and Resources
References:
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- : "Pathological roles of MAPK signaling pathways in human diseases." in: Biochimica et biophysica acta, Vol. 1802, Issue 4, pp. 396-405, (2010) (PubMed).
- : "The MAPK signaling cascade." in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 9, Issue 9, pp. 726-35, (1995) (PubMed).
- : "Pathological roles of MAPK signaling pathways in human diseases." in: Biochimica et biophysica acta, Vol. 1802, Issue 4, pp. 396-405, (2010) (PubMed).
- : "Compromised MAPK signaling in human diseases: an update." in: Archives of toxicology, Vol. 89, Issue 6, pp. 867-82, (2016) (PubMed).
- : "MAPK signal pathways in the regulation of cell proliferation in mammalian cells." in: Cell research, Vol. 12, Issue 1, pp. 9-18, (2004) (PubMed).
