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FLASH GENE

Symbol

S100A8

contributors: mct - updated : 23-02-2015

HGNC name	S100 calcium binding protein A8 (calgranulin A)
HGNC id	10498

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       highly Cardiovascular heart       highly Respiratory lung       highly Skin/Tegument skin         Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial barrier lining epidermis     Homo sapiens Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic monocyte Homo sapiens Blood/Hematopoietic neutrophil Homo sapiens Lymphoid/Immune macrophage Homo sapiens Skin/Tegument keratinocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two calcium binding domains with an EF-hand motif
	one S100 specific N terminus
	one classical C terminus

mono polymer

homomer , heteromer , dimer

HOMOLOGY

interspecies

homolog to murine S100a8

Homologene

FAMILY

S100A8 protein family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton

basic FUNCTION	involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation (epidermal differentiation)
	involved in the development of epithelial skin tumors
	playing a role in the inflammatory response to lipopolysaccharide by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site
	playing a pivotal role during sepsis
	S100A8/S100A9 levels are likely to be maintained in conditions where IL10 is raised, and these proteins may contribute to viral persistence in patients infected by some RNA viruses
	bacterial flagellin induces the upregulation of S100A8/S100A9 via a TLR5-dependent mechanism in epidermal keratinocytes (PMID/
	cytokine-induced potentiated S100A8 and S100A9 expression under conditions, is able to aggravate proinflammatory conditions via activation of the AGER pathway
	is a potent chemoattractant and also an anti-oxidant, and both roles may be important in the developing placenta
	pivotal roles of S100A8 and S100A9 in the propagation of inflammation and keratinocyte proliferation in psoriasis
	S100A8 and S100A9 themselves function as pro-angiogenic and chemotactic factors, generating a psoriatic milieu in skin
	S100A8 and/or S100A9 promote endothelial cell proliferation, survival, and angiogenesis both directly and by inducing keratinocytes to produce pro-angiogenic cytokines
	S100A8 and S100A9 are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer
	S100A8/A9 (calprotectin) negatively regulates G2/M cell cycle progression and growth of squamous cell carcinoma
	role for S100A8 and S100A9 in redox-sensitive biological responses, including pro-inflammatory cytokine secretion
	S100A8/A9 (calprotectin) and S100A12 proinflammatory mediators are found at inflammatory sites and in the serum of patients with inflammatory or autoimmune diseases

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	constituent of epidermal differentiation complex
	heterodimerizing with S100A9 for NADPH oxidase activation in neutrophils
	S100A8/S100A9-heterodimers are formed in the absence of calcium, tetramerization is strictly calcium-dependent

INTERACTION

DNA

RNA

small molecule	metal binding,
	Ca2+

protein	interacting with S100A9 (S100A8-S100A9 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes)
	interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4
	S100A8 and S100A9 interact non-covalently, and that they function coordinately and/or independently as homodimers or heterodimers, depending on the microenvironment
	functional partner for NADPH oxidase activation contrary to S100A9, however, the loading with calcium and a combination with phosphorylated S100A9 are essential
	S100A12, S100A8, S100A9 has no direct effect on cholesterol efflux in macrophages, but rather promotes the secretion of IL22, which then directly reduces cholesterol efflux in macrophages by decreasing the expression of ABCG1

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in psoriasis and in epithelial skin tumors constitutional     --over   in numerous inflammatory diseases, such as sepsis, rheumatoid arthritis, inflammatory bowel disease, vasculitis and cancer constitutional     --low   in placentas of preeclampsia and HELLP syndrome (Buimer 2008) tumoral     --over   elevated levels of S100A8 or A9 in the ductal fluid, a near absence of pancreatic enzymes, and high levels of mucins were found to have significantly worse prognosis in pancreatic cancer constitutional     --over   overexpression of S100A8-S100A9 in neurons is an early step in oncogenic KRAS-induced gliosis

Susceptibility

to rheumatoid arthritis

Variant & Polymorphism

Candidate gene	for lipodystrophy and diabetes
Marker	S100A8 and S100A9 may serve as biomarkers for the detection of renal cell carcinoma
	potential marker of disease activity in patients with psoriatic arthritis
	dysregulated levels of S100A8 gene may be involved in sepsis pathophysiology and may be utilized as potential diagnostic biomarkers
Therapy target
	System Type Disorder Pubmed dermatology skin   inhibiting S100A8 and/or S100A9 may be a novel therapy targeting various molecular events involved in the initiation of psoriasis cancer urinary   attractive anticancer target for therapeutic intervention in kidney cancer

ANIMAL & CELL MODELS

S100a8 (-/-) condition is embryonic lethal