InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: S100A9

Summary

InnateDB Protein

IDBP-102646.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

S100A9

Protein Name

S100 calcium binding protein A9

Synonyms

60B8AG; CAGB; CFAG; CGLB; L1AG; LIAG; MAC387; MIF; MRP14; NIF; P14;

Species

Homo sapiens

Ensembl Protein

ENSP00000357727

InnateDB Gene

IDBG-102644 (S100A9)

Protein Structure

UniProt Annotation

Function

S100A9 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, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism. 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, transferring 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. {ECO:0000269PubMed:12626582, ECO:0000269PubMed:15331440, ECO:0000269PubMed:15598812, ECO:0000269PubMed:15642721, ECO:0000269PubMed:16258195, ECO:0000269PubMed:19087201, ECO:0000269PubMed:19122197, ECO:0000269PubMed:19402754, ECO:0000269PubMed:19534726, ECO:0000269PubMed:19935772, ECO:0000269PubMed:20103766, ECO:0000269PubMed:21325622, ECO:0000269PubMed:21487906, ECO:0000269PubMed:22363402, ECO:0000269PubMed:22804476, ECO:0000269PubMed:22808130, ECO:0000269PubMed:8423249}.

Subcellular Localization

Secreted. Cytoplasm. Cytoplasm, cytoskeleton. Cell membrane; Peripheral membrane protein. Note=Predominantly localized in the cytoplasm. Upon elevation of the intracellular calcium level, translocated from the cytoplasm to the cytoskeleton and the cell membrane. Upon neutrophil activation or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway.

Disease Associations

Tissue Specificity

Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers. {ECO:0000269PubMed:15598812, ECO:0000269PubMed:3313057, ECO:0000269PubMed:3405210, ECO:0000269PubMed:8423249, ECO:0000269PubMed:9083090}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 97 experimentally validated interaction(s) in this database.

Experimentally validated
Total	97 [view]
Protein-Protein	96 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004871	signal transducer activity
GO:0005509	calcium ion binding
GO:0005515	protein binding
GO:0008017	microtubule binding
GO:0008270	zinc ion binding
GO:0016209	antioxidant activity
GO:0035662	Toll-like receptor 4 binding
GO:0050544	arachidonic acid binding
GO:0050786	RAGE receptor binding

Biological Process

GO:0001816	cytokine production
GO:0002523	leukocyte migration involved in inflammatory response
GO:0002544	chronic inflammatory response
GO:0006914	autophagy
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0006954	inflammatory response
GO:0007165	signal transduction
GO:0007267	cell-cell signaling
GO:0010043	response to zinc ion
GO:0030307	positive regulation of cell growth
GO:0030593	neutrophil chemotaxis
GO:0030595	leukocyte chemotaxis
GO:0031532	actin cytoskeleton reorganization
GO:0032119	sequestering of zinc ion
GO:0032496	response to lipopolysaccharide
GO:0032602	chemokine production
GO:0042742	defense response to bacterium
GO:0045087	innate immune response (InnateDB)
GO:0045113	regulation of integrin biosynthetic process
GO:0045471	response to ethanol
GO:0050729	positive regulation of inflammatory response
GO:0050832	defense response to fungus
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0051493	regulation of cytoskeleton organization
GO:0070488	neutrophil aggregation
GO:2001244	positive regulation of intrinsic apoptotic signaling pathway

Cellular Component

GO:0005576	extracellular region
GO:0005615	extracellular space
GO:0005634	nucleus
GO:0005829	cytosol
GO:0005856	cytoskeleton
GO:0005886	plasma membrane
GO:0070062	extracellular vesicular exosome