. 2020 Jul 24;12(8):2037. doi: 10.3390/cancers12082037

Table A1.

Summary of the S100 family members.

Family Member	Expression	Regulation	Targets/Interaction	Function	References
S100A1	Cardiomyocytes, skeletal muscle cells, endothelial cells, neurological cells	Transcription factor binding sites for Nkx 2.5, Mef2 and CEF	SERCA2a/PLB, RyR2, F₁-ATPase, ANT, Titin	Modulates contractile performance in cardiomyocytes: interaction with SERCA2a/PLB and RyR2 improves systolic Ca²⁺ release and diastolic Ca²⁺ uptake; binding to the PEVK subdomain of titin results in improved sarcomeric compliance Mitochondrial metabolism: plays a role in cardiac energy homeostasis by interacting with F₁-ATPase and ANT	[36,37,256]
S100A2 (S100L; CaN19)	Epithelial tissue	Transcriptional activation by p53 EGF-induced transcription in keratinocytes	p53, RAGE	Tumour suppressor: calcium-dependent activation of p53	[51,78]
S100A3 (S100E)	Hair cuticular cells	PAD3 induces the formation of a homotetramer via citrullination	RARα	Maintenance of the hair texture: Ca²⁺-dependent epithelial barrier formation and cuticular maturation	[22,257,258]
S100A4 (metastasin; CAPL; calvasculin)	Fibroblasts, immune cells, cancer cells	Transcription is promoted by β-catenin and growth factors	actin, NMIIA, tropomyosin, p53, p37, MMP2, liprin-β1, RAGE, TLR4, EGFR, IL-10 receptor, annexin II	Cell migration: interaction with proteins of the cytoskeleton and induces secretion of matrix metalloproteinases (MMPs) Cell growth and proliferation: activates NF-κB and MAP kinases	[45,52,89]
S100A5	olfactory bulb, brainstem, spinal trigeminal tract	-	RAGE, NCXI	-	[34,259]
S100A6 (Calcylin; Cacy; CABP; PRA)	Fibroblasts, epithelial cells	Extracellular by PDGF, EGF, retonic acid, estrogen, gastrin Under stress conditions: ischemia, irradiation, oxidative stress Intracellular: NF-κB activates S100A6-promotor, while p53 indirectly suppresses transcription	caldesmon, calponin, tropomyosin, kinesin light chain, RAGE	Control of cell cycle progression: involved in ubiquitination of β-catenin Regulation of microfilament dynamics: interaction with proteins of the cytoskeleton Neuronal apoptosis: binding to RAGE leads to ROS-dependent activation of JNK, caspase-3, and caspase-7 As extracellular factor: involved in the release of lactogen II, insulin, and histamine	[27,260]
S100A7 (Psoriasin)	Keratinocytes	Secretion induced by disruptive stimuli (e.g., UVB, irradiation, retonic acid, infection with bacteria) Upregulated by pro-inflammatory cytokines (e.g., IL-1α, TNFα, IL-17, IL-22)	RAGE, FABP, TGM	Role as AMP: lyses bacteria (e.g., E. coli) Inhibition of epidermal differentiation: RAGE-dependent activation of NF-κB-signaling results in upregulation of IL-6 Inflammation: selective chemotactic for CD4⁺ lymphocytes and neutrophils	[28,42]
S100A8 (Calgranulin A)	Neutrophils, osteoclasts, hypertrophic chondrocytes, myeloid dendric cells	Induced by LPS, IL-10, TLR4, glucocorticoids	Telomerase	Inflammation: chemotactic for neutrophils, protects from oxidation by scavenging oxidants, acts as NO shuttle, thereby activating mast cells Regulation of differentiation: binds and inhibits telomerase, therefore promoting differentiation in keratinocytes	[43,261]
S100A9 (Calgranulin B)	Neutrophil granulocytes, monocytes	Upregulated by glucocorticoids, cytokines, and growth factors	RAGE, TLR4	Inflammation: Zn²⁺-dependent interaction with RAGE and TLR4 leads to upregulation of pro-inflammatory cytokines (e.g., TNFα) via NF-κB signalling; acts as a chemoattractant and is involved in differentiation of myeloid cells	[21,40,43]
S100A8/S100A9 (Calprotectin)	Neutrophils, monocytes, macrophages, inducible expression in keratinocytes and epithelial cells (e.g., under inflammatory conditions)	TNFα, IL-1β, HIF-1 stimulate expression Secretion is Ca²⁺-dependent	RAGE, TLR4	Modulation of the cytoskeleton: interacts with several proteins of the cytoskeleton (e.g., keratin and F-actin) and promotes polymerisation of microtubules Protection against pathogens: S100A8/S100A9 expressing epithelial cells are more resistant to bacterial infection Inflammation: RAGE- and TLR4-mediated upregulation of pro-inflammatory cytokines (e.g., IL-6 and IL-8) and adhesion proteins (e.g., ICAM-1)	[29]
S100A10 (p11)	Endothelial cells, macrophages, fibroblasts, epithelial cells	The expression can be induced by: Sp1, IFN-γ, glucocorticoids, TGFβ, EGF, IL-1β, thrombin, oncogenes (e.g., PML-RARα, KRas)	Annexin II, 5-HT1B receptor, TRPV5, TRPV6, TASK-1	Role as plasminogen receptor: regulates plasmin production by forming a complex with annexin II, which leads to fibrinolysis, activation of MMPs, ECM degradation, stimulation of the JAK1/TYK2 signalling pathway, and recruitment of macrophages Trafficking of plasma membrane proteins: S100A10 interacts with the 5-HT1B receptor, TRPV5, TRPV6, and TASK-1 and participates in their trafficking	[13,35]
S100A11 (S100C; calgizzarin)	Chondrocytes, keratinocytes, fibroblasts, luteal cells	TGFβ and high extracellular Ca²⁺ concentrations stimulate expression and activity	RAGE, annexin I, nucleolin	Cell growth regulation: intracellular S100A11 inhibits cell growth by binding to nucleolin, which allows expression of p21, leading to inhibition of DNA synthesis; extracellular S100A11 promotes cell proliferation by RAGE-mediated transcription of EGF Interaction with RAGE: RAGE activates p38 MAPK kinase, which increases type X collagen	[49,50]
S100A12 (Calgranulin C; EN-RAGE)	Neutrophil granulocytes, monocytes, macrophages, early-stage differentiating epithelial and dendric cells	Upregulated by TNFα and LPS Secretion in neutrophils involves ROS and K⁺ exchange	RAGE, TLR4, CacyBP/SIP	Wnt signalling: binds to CacyBP/SIP and is part of the ubiquitinylation complex Inflammation: binding to TLR4 leads to activation and migration of monocytes and release of IL-1β, IL-6, and IL-8, RAGE-mediated NF-κB and MAPK signalling induces secretion of TNFα and IL-1β Inhibition of pathogens: antifungal and antibacterial activity via Zn²⁺ sequestration	[41,262,263,264]
S100A13	Leydig cells of testis, follicle cells of thyroid, smooth muscle, endothelial and epithelial cells	Induced by stress stimuli	RAGE, Syt1, SPHK1	Non-canonical secretion pathway: forms a copper-dependent multiprotein complex with Syt1 and SPHK and is thereby involved in the non-classical stress-dependent release of FGF-1, IL-1α, and prothymosin-α	[265,266,267]
S100A14	High expression in epithelial tissue, lower expression in mesenchymal tissue	Regulated by p53	RAGE, p53	Interaction with RAGE: binding in lower concentrations activates MAPK and NF-κB signalling, leading to cell proliferation; binding in high concentrations activates ROS production, resulting in apoptosis	[46,53]
S100A15 (S100A7A; koebnerisin)	Dendric cells, endothelial cells, vascular smooth muscle cells, peripheral nerves, keratinocytes	Upregulated by E. coli through TLR4 Transcription can be induced by IFN-γ, IL-1β, TNFα, and Th1 Co-expression with S100A7 in keratinocytes	GPCR	Epidermal cell maturation: upregulated in epidermal differentiation Initial immune response: functions as an antibacterial agent by reducing the survival of E. coli and other strains Inflammation: acts as a chemoattractant for leucocytes via GPCR	[23,268]
S100A16	Astrocytes, adipocytes	Ca²⁺ influences nuclear import/export	p53	Overexpression in preadipocytes resulted in increased proliferation and reduction in insulin-stimulated glucose uptake and Akt phosphorylation	[269,270]
S100B	Astrocytes, oligodendrocytes, Schwann cells, ependymal cells, melanocytes, adipocytes, chondrocytes	Secretion is regulated by IL-1β, extracellular Ca²⁺ and K⁺, inhibitors of gap junctions, antioxidants, lipopolysaccharide, and apomorphine p53 upregulates expression	Extracellular: RAGE, FGFR1 Intracellular: Ndr kinase, Src, Rac1, IQGAP1, p53	Cell migration: regulates F-actin-based cytoskeleton via Src, IQGAP1, and Rac1 Cell division: interaction with Ndr kinase leads to the promotion of PI3K/Akt signalling Role in tumour suppression: inhibits p53 activity and reduces p53 Proliferation: at higher concentrations, S100B blocks RAGE and stimulates FGFR1, leading to Ras/MEK/Erk-mediated proliferation; at low concentrations, S100B additionally stimulates RAGE-mediated p38 MAPK signalling, resulting in activation of the mitogenic program	[47,65,271]
100G (CaBP-9k)	Epithelial cells	Vitamin D-dependent in the intestine	-	Cellular Ca²⁺ homeostasis: regulates intracellular Ca²⁺ levels and prevents toxic concentrations	[33]
S100P	Epithelial cells, leucocytes,	Promoter has binding sites for SMAD, STAT/CREB, and SP/KLF During embryonic implantation: highly expressed in the trophoblastic layer of the embryo, and in the endometrium of the uterine wall	RAGE, IQGAP1, enzrin, NMIIA	Cell proliferation and survival: activates RAGE-mediated NF-κB signalling; interaction with IQGAP1 induces MAPK signalling cascade Cell migration: promotes interaction with F-actin (via enzrin) and reduces focal adhesion sites (via NMIIA)	[48,272]
S100Z	Leucocytes	-	-	-	[8]