S100A8: S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH- oxidase by facilitating the enzyme complex assembly at the cell membrane, transfering arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinfammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF- kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. Belongs to the S-100 family.
Chromosomal Location of Human Ortholog: 1q21
Cellular Component: cytoskeleton; cytosol; extracellular region; extracellular space; nucleus; plasma membrane
Molecular Function: arachidonic acid binding; calcium ion binding; microtubule binding; protein binding; RAGE receptor binding; zinc ion binding
Biological Process: activation of NF-kappaB transcription factor; acute inflammatory response; astrocyte development; autophagy; caspase activation; chemokine production; chronic inflammatory response; cytokine production; defense response to bacterium; defense response to fungus; inflammatory response; innate immune response; leukocyte migration during inflammatory response; neutrophil chemotaxis; peptidyl-cysteine S-nitrosylation; positive regulation of cell growth; positive regulation of inflammatory response; positive regulation of peptide secretion; regulation of cytoskeleton organization and biogenesis; response to ethanol; response to lipopolysaccharide; response to zinc ion; sequestering of zinc ion; wound healing
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