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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
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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
    SystemTypeDisorderPubmed
    dermatologyskin 
    inhibiting S100A8 and/or S100A9 may be a novel therapy targeting various molecular events involved in the initiation of psoriasis
    cancerurinary 
    attractive anticancer target for therapeutic intervention in kidney cancer
    ANIMAL & CELL MODELS
  • S100a8 (-/-) condition is embryonic lethal