Affinage

S100A16

Protein S100-A16 · UniProt Q96FQ6

Round 2 corrected
Length
103 aa
Mass
11.8 kDa
Annotated
2026-04-28
84 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

S100A16 is an EF-hand Ca²⁺-binding protein that functions as a Ca²⁺-dependent signaling hub linking nucleolar ribosome biogenesis, epithelial–mesenchymal transition, adipogenesis, and organ fibrosis. Structurally, it forms a homodimer that binds Ca²⁺ exclusively through the C-terminal EF-hand, with minimal conformational change upon Ca²⁺ binding owing to strong inter-helical hydrophobic contacts (PMID:17030513, PMID:21046186). In the nucleus, S100A16 associates with RNA Polymerase I at rDNA loci to promote rRNA synthesis and metastasis (PMID:40846689); Ca²⁺ elevation drives its translocation to the cytoplasm, where it engages diverse partners—p53 (promoting its degradation to drive adipogenesis and hepatic stellate cell activation) (PMID:21266506, PMID:35914619), GRP78 (competitively releasing IRE1α to activate ER stress) (PMID:34645789), myosin-9 (reorganizing the actin cytoskeleton during renal EMT) (PMID:32094322), calmodulin (dysregulating the CaMKK2/AMPK axis) (PMID:31069793, PMID:39613175), and the E3 ligase HRD1 (ubiquitinating GSK3β/CK1α to activate Wnt/β-catenin signaling in kidney injury) (PMID:35279748). S100A16 protein levels are post-translationally stabilized by heterodimerization with S100A14, and its transcription is directly activated by TFAP2B and NF-κB/p65 and repressed by estrogen signaling (PMID:24086685, PMID:38710691, PMID:33921267, PMID:24501224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Established that S100A16 is a homodimeric Ca²⁺-binding protein using only the C-terminal EF-hand, answering the fundamental question of how this atypical S100 member senses calcium and revealing its Ca²⁺-dependent nucleolar-to-cytoplasmic translocation.

    Evidence Recombinant protein flow dialysis, Trp fluorescence spectroscopy, immunofluorescence in glioblastoma cells

    PMID:17030513

    Open questions at the time
    • Target-binding surface only inferred from hydrophobic patch exposure; no target protein identified
    • Mouse S100A16 did not expose a hydrophobic patch—species-specific functional differences unresolved
  2. 2010 High

    Atomic-resolution structures of apo and Ca²⁺-bound S100A16 explained why Ca²⁺-induced conformational change is unusually modest, resolving the paradox of weak target-protein interaction detected biochemically.

    Evidence Dual NMR solution structure and X-ray crystallography of human S100A16

    PMID:21046186

    Open questions at the time
    • No structure of S100A16 bound to a target peptide or protein
    • Functional consequence of minimal conformational change for downstream signaling not tested
  3. 2011 High

    Identified the first cellular function—promotion of adipogenesis—and the first direct binding partner, p53, establishing that S100A16 suppresses p53-dependent transcription and that Ca²⁺-induced cytoplasmic translocation regulates this adipogenic activity.

    Evidence Overexpression/RNAi in 3T3-L1 preadipocytes; co-immunoprecipitation of S100A16–p53; Ca²⁺ ionophore translocation

    PMID:21266506 PMID:21871643

    Open questions at the time
    • Mechanism of p53 degradation not defined (direct or via E3 ligase)
    • Whether Ca²⁺-dependent translocation is required for all S100A16 functions unclear
  4. 2013 High

    Revealed that S100A14 heterodimerizes with S100A16 and stabilizes it post-translationally, and that S100A16 reciprocally regulates mesenchymal stem cell fate by promoting adipogenesis via JNK and inhibiting osteogenesis via ERK1/2.

    Evidence Yeast two-hybrid, co-IP, cycloheximide chase (S100A14–S100A16); luciferase reporters for PPARγ/RUNX2 in BM-MSCs

    PMID:23526364 PMID:24086685

    Open questions at the time
    • Degradation pathway for S100A16 protein itself not identified (proteasome- and lysosome-independent)
    • S100A14–S100A16 stoichiometry and structural basis unresolved
  5. 2014 Medium

    Extended S100A16 function to cancer EMT: in breast cancer cells it drives Notch1-dependent E-cadherin loss, and estrogen signaling was shown to directly repress the S100A16 promoter, linking hormonal regulation to its adipogenic and EMT roles.

    Evidence Retroviral overexpression/Notch1 siRNA rescue in MCF-7; luciferase reporter for E2-mediated S100A16 promoter repression; ovariectomized rat model

    PMID:24501224 PMID:25287362

    Open questions at the time
    • Notch1 activation mechanism by S100A16 not defined (direct interaction vs. transcriptional)
    • Estrogen receptor subtype mediating S100A16 repression not identified
  6. 2018 High

    Demonstrated that exosome-transferred S100A16 protects cancer cells from apoptosis via mitochondrial membrane potential maintenance dependent on prohibitin-1, and that S100A16 suppresses proteasomal degradation of p53 to maintain cancer stemness factors Oct4/Nanog.

    Evidence HBMEC exosome transfer to SCLC cells with PHB-1 epistasis; cervical carcinoma spheroid assay with proteasome inhibitor rescue

    PMID:29928366 PMID:30183374

    Open questions at the time
    • Direct S100A16–PHB1 physical interaction not tested
    • Contradictory roles of S100A16 on p53 (degradation in adipogenesis vs. stabilization in stemness) not reconciled
  7. 2019 Medium

    Identified calmodulin as a direct S100A16 interactor mediating hepatic lipogenesis via the CaMKK2/AMPK axis, and placed S100A16 downstream of Snail in a chemoresistance circuit operating through AKT/Bcl-2.

    Evidence Co-IP (S100A16–CaM) in transgenic/knockout mice on HFD; siRNA knockdown in drug-resistant bladder cancer cells

    PMID:31069793 PMID:31118765

    Open questions at the time
    • Whether S100A16 competes with Ca²⁺/CaM targets or modulates CaM conformation not distinguished
    • Snail–S100A16 transcriptional regulation not confirmed by promoter binding assay
  8. 2020 High

    Identified myosin-9 as a Ca²⁺-dependent S100A16 partner driving actin cytoskeletal reorganization and renal EMT, validated in transgenic and knockout mice undergoing ureteral obstruction.

    Evidence Mass spectrometry pulldown for S100A16 partners; UUO model in S100A16 transgenic/heterozygous-KO mice; F-actin immunofluorescence

    PMID:32094322

    Open questions at the time
    • Binding interface on myosin-9 and whether S100A16 modulates myosin ATPase activity unknown
    • Relative contribution of myosin-9 vs. GRP78 pathways in renal fibrosis not delineated
  9. 2021 High

    Defined a competitive binding mechanism at the ER: S100A16 sequesters GRP78 away from IRE1α, triggering IRE1α autophosphorylation and XBP1 splicing, establishing S100A16 as a Ca²⁺-dependent activator of the unfolded protein response in renal fibrosis.

    Evidence Co-IP showing competitive S100A16–GRP78 vs. IRE1α–GRP78 binding; BAPTA-AM reversal; UUO mouse model

    PMID:34645789

    Open questions at the time
    • Whether S100A16–GRP78 interaction occurs at other ER stress branches (PERK, ATF6) not tested
    • Structural basis for GRP78 competition not resolved
  10. 2021 Medium

    Placed S100A16 downstream of NF-κB/p65 transcriptional control in gastric cancer, and identified ZO-2 as an interaction partner whose ubiquitin-dependent degradation drives S100A16-mediated EMT and invasion.

    Evidence Dual-luciferase reporter for NF-κB at S100A16 promoter; ADAMTS19–P65 co-IP; proteomic identification and co-IP of S100A16–ZO-2; ubiquitination assay

    PMID:33921267 PMID:34650982

    Open questions at the time
    • E3 ligase responsible for ZO-2 ubiquitination downstream of S100A16 not identified
    • Whether NF-κB regulation of S100A16 is tissue-general or gastric cancer–specific unknown
  11. 2022 High

    Established that S100A16 binds p53 to promote its degradation in hepatic stellate cells, driving CXCR4/ERK/AKT-dependent liver fibrosis, and that HRD1-mediated ubiquitination of GSK3β/CK1α downstream of S100A16 activates Wnt/β-catenin signaling in acute kidney injury—both validated by genetic knockout in vivo.

    Evidence S100A16-KO and transgenic mice in liver fibrosis and renal IRI models; co-IP (S100A16–p53); ubiquitination assays (HRD1–GSK3β/CK1α); Wnt inhibitor epistasis

    PMID:35279748 PMID:35914619

    Open questions at the time
    • Whether S100A16 directly activates HRD1 E3 ligase activity or recruits substrates not distinguished
    • How p53 degradation is mechanistically accomplished (proteasomal pathway involvement) remains incomplete
  12. 2024 High

    Identified TFAP2B as a direct transcriptional activator of S100A16 via ChIP, and confirmed that S100A16–calmodulin interaction mediates cardiomyocyte injury after ischemia/reperfusion through the CaMKK2/AMPK pathway downstream of NF-κB/p65 promoter activation.

    Evidence ChIP and luciferase assay (TFAP2B at S100A16 promoter; HIF-1α at HRD1 promoter); S100A16-KO rat cells; myocardial IRI model with adenoviral knockdown

    PMID:38710691 PMID:39613175

    Open questions at the time
    • Whether TFAP2B and NF-κB/p65 cooperate at the S100A16 promoter or act in distinct tissues not tested
    • Upstream signals activating TFAP2B in hypoxia not defined
  13. 2025 High

    Revealed that S100A16 localizes to the nucleolus and associates with RNA Polymerase I at rDNA loci, directly promoting rRNA synthesis; its loss reverses EMT and reduces metastasis, connecting ribosome biogenesis to the metastatic program.

    Evidence ChIP-MS (S100A16 at rDNA with RPA194); rRNA synthesis assay; CRISPR knockout; in vivo metastasis model in breast cancer

    PMID:40846689

    Open questions at the time
    • Mechanism by which S100A16 activates Pol I (cofactor recruitment vs. chromatin remodeling) not defined
    • Whether nucleolar function is Ca²⁺-dependent or constitutive not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for S100A16 target discrimination among its many partners, how its apparently opposing effects on p53 (degradation in adipogenesis/fibrosis vs. stabilization in stemness) are contextually regulated, and the relative contribution of nucleolar rRNA synthesis versus cytoplasmic EMT pathways to its pro-metastatic activity.
  • No co-crystal structure of S100A16 with any target protein
  • Context-dependent p53 regulation mechanism unresolved
  • Relative importance of nuclear vs. cytoplasmic functions in different disease settings not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005730 nucleolus 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-8953854 Metabolism of RNA 1
Partners
CALM1HSPA5MOV10MYH9POLR1AS100A14SYVN1TP53
Complex memberships
S100A14/S100A16 heterodimerS100A16 homodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 S100A16 is a homodimeric EF-hand Ca²⁺-binding protein that binds two Ca²⁺ ions per dimer exclusively via the C-terminal EF-hand of each subunit (the N-terminal EF-hand lacks the conserved glutamate and is non-functional). Ca²⁺ binding induces conformational changes detected by Trp fluorescence, and in human S100A16 (but not mouse) a hydrophobic patch implicated in target-protein recognition is formed upon Ca²⁺ binding. In glioblastoma cells S100A16 accumulates in nucleoli and translocates to the cytoplasm upon Ca²⁺ stimulation. Recombinant protein purification, flow dialysis (Ca²⁺ binding stoichiometry/affinity), Trp fluorescence spectroscopy, in situ hybridization, immunohistochemistry, immunofluorescence localization The Journal of biological chemistry High 17030513
2010 The homodimeric structure of human S100A16 was determined both in the apo and Ca²⁺-bound states by NMR and X-ray crystallography. Unlike most S100 proteins, the conformational rearrangement upon Ca²⁺ binding is minor, attributable to the absence of the glutamate residue at the end of the N-terminal EF-hand and to unusually strong hydrophobic interactions between helices 3 and 4 that stabilize the 'closed' conformation of the second EF-hand even after Ca²⁺ binding. NMR solution structure (apo and Ca²⁺-bound), X-ray crystallography (solid state); structures compared to functional Ca²⁺-binding data Journal of biological inorganic chemistry High 21046186
2011 S100A16 promotes adipogenesis and preadipocyte proliferation: overexpression in 3T3-L1 cells markedly enhances differentiation into adipocytes while reducing insulin-stimulated glucose uptake and AKT phosphorylation; siRNA knockdown inhibits adipogenesis. Immunoprecipitation showed S100A16 physically interacts with the tumor suppressor p53; S100A16 overexpression suppresses p53-responsive genes and knockdown activates them. Elevation of intracellular Ca²⁺ via ionophore causes nuclear exclusion of S100A16. Overexpression and RNAi in 3T3-L1 preadipocytes; Oil Red O staining; glucose uptake assay; AKT phosphorylation Western blot; co-immunoprecipitation (S100A16–p53); Ca²⁺ ionophore treatment with localization imaging Endocrinology High 21266506
2011 High-calcium diet reduces nuclear S100A16 levels in 3T3-L1 preadipocytes (Ca²⁺ ionophore-induced nuclear exclusion), correlating with inhibition of adipogenesis and enhanced insulin sensitivity, demonstrating that Ca²⁺-driven cytoplasmic translocation of S100A16 is the mechanistic link between dietary calcium and adipogenesis suppression. Obese rat model; Western blot for S100A16 expression; 3T3-L1 preadipocyte Ca²⁺ ionophore treatment with subcellular localization; Oil Red O staining; AKT phosphorylation Metabolism: clinical and experimental Medium 21871643
2013 S100A16 physically interacts with S100A14 as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and double immunofluorescence. S100A14 overexpression leads to post-transcriptional upregulation of S100A16 protein (no change in mRNA), while S100A16 overexpression does not reciprocally upregulate S100A14, establishing a unidirectional regulatory relationship. Protein degradation of both S100A14 and S100A16 is independent of proteasomal and lysosomal pathways. Yeast two-hybrid screen; co-immunoprecipitation; double indirect immunofluorescence; cycloheximide chase assay; proteasome/lysosome inhibitor experiments; qRT-PCR and Western blot PloS one High 24086685
2013 In bone marrow-derived mesenchymal stem cells (BM-MSCs), S100A16 overexpression stimulates adipogenesis and inhibits osteogenesis: it increases PPARγ promoter activity and decreases RUNX2 promoter activity. The ERK1/2 pathway mediates osteogenesis regulation whereas the JNK pathway mediates adipogenesis regulation by S100A16. S100A16 transgenic and knockout BM-MSCs; Oil Red O and Alizarin Red S staining; luciferase reporter assays (PPARγ and RUNX2 promoters); Western blot for p-ERK1/2 and p-JNK; RT-PCR for BMP2, RUNX2, PPARγ, C/EBPα Molecular biology reports Medium 23526364
2014 S100A16 overexpression in MCF-7 breast cancer cells upregulates Notch1, ZEB1, and ZEB2, which repress E-cadherin and β-catenin and increase N-cadherin and vimentin (EMT markers). Notch1 siRNA knockdown reverses the EMT induced by S100A16 overexpression, placing Notch1 as a critical downstream effector of S100A16-driven EMT. Retroviral overexpression in MCF-7; siRNA knockdown of Notch1; Western blot and qRT-PCR for EMT markers; proliferation, colony formation, migration, and invasion assays Journal of biomedical science Medium 25287362
2014 Estrogen (E2) suppresses adipogenesis by inhibiting S100A16 expression; luciferase assay showed E2 directly inhibits the S100A16 promoter. Overexpression of S100A16 reversed E2-induced inhibition of adipogenesis, placing S100A16 downstream of estrogen signaling in adipogenic regulation. Ovariectomized rat model; mouse embryonic fibroblast adipogenesis assay; luciferase reporter assay (S100A16 promoter); S100A16 overexpression rescue experiment; Western blot for PPARγ, aP2, C/EBPα, S100A16 Journal of molecular endocrinology Medium 24501224
2015 In oral squamous cell carcinoma (OSCC), S100A16 overexpression promotes differentiation and acts as a tumor suppressor: it reduces cell proliferation, sphere formation, 3D-invasive ability, and tumorigenesis in a mouse xenograft model. Mechanistically, S100A16 overexpression downregulates self-renewal markers Bmi-1 and Oct4A and invasion-related MMP1 and MMP9, while knockdown has opposite effects. Retroviral overexpression and knockdown in CaLH3 and H357 cells; proliferation, sphere formation, 3D organotypic invasion assays; mouse xenograft model; Western blot and qRT-PCR for differentiation, self-renewal, and invasion markers BMC cancer High 26353754
2016 S100A16 promotes prostate cancer cell invasion, migration, and proliferation via activation of AKT and ERK signaling pathways and downstream downregulation of tumor suppressors p21 and p27. Specific inhibitors of AKT (LY294002) and ERK (PD98059) suppressed the S100A16-induced clone formation and invasion, functionally confirming pathway placement. Stable overexpression and shRNA knockdown in DU-145/PC-3 cells; Transwell invasion/migration, wound healing, colony formation; Western blot for p-AKT, p-ERK, p21, p27; pharmacological pathway inhibition Tumour biology Medium 27240591
2018 Brain microvascular endothelial cell (HBMEC) exosomes transfer S100A16 protein to SCLC cells, inducing its elevation and translocation from the cytoplasm to the nucleus. Elevated S100A16 in SCLC cells prevents loss of mitochondrial membrane potential (Δψm) and confers resistance to apoptosis under stress. This protective effect depends on prohibitin (PHB)-1, a mitochondrial inner membrane protein: PHB-1 siRNA knockdown in S100A16-overexpressing cells abolishes the protective phenotype, placing PHB-1 downstream of S100A16 in mitochondrial protection. Co-culture with HBMEC; GW4869 exosome-release inhibition; ultracentrifugation-purified exosome treatment; Western blot and immunofluorescence for S100A16 localization; Annexin V/PI apoptosis assay; JC-1 mitochondrial membrane potential assay; PHB-1 siRNA epistasis FASEB journal High 30183374
2018 In cancer stem-like spheroid cells from Yumoto cervical carcinoma, S100A16 positively regulates the stem cell transcription factors Oct4 and Nanog at the protein level. S100A16 knockdown decreases Oct4 and Nanog protein and reduces spheroid size. The proteasome inhibitor lactacystin blocks the S100A16-knockdown-induced decrease of Oct4/Nanog protein, indicating that S100A16 normally suppresses proteasomal degradation of p53 (which in turn represses Oct4/Nanog). Sphere formation assay; siRNA knockdown of S100A16; RT-PCR and Western blot for Oct4, Nanog, p53, S100A16; proteasome inhibitor lactacystin treatment Oncology letters Medium 29928366
2019 S100A16 interacts with calmodulin (CaM) and through this interaction regulates the AMPK signaling pathway (CaM/CAMKK2/AMPK) to promote hepatic lipid synthesis. S100A16 transgenic mice on high-fat diet develop significantly more severe fatty liver than wild-type, while knockdown mice are protected, confirming in vivo lipogenic function. S100A16 transgenic and knockdown C57BL/6 mice on HFD/NFD; serum TG and liver histology; co-immunoprecipitation (S100A16–calmodulin); RNA sequencing; Western blot for AMPK pathway proteins Journal of cellular physiology Medium 31069793
2019 In bladder cancer chemoresistance, S100A16 expression is transcriptionally regulated by the EMT transcription factor Snail. S100A16 knockdown suppresses the AKT/Bcl-2 pathway, promotes apoptosis, and resensitizes mitomycin-C-resistant cells to the drug, placing S100A16 in a Snail → S100A16 → AKT/Bcl-2 anti-apoptosis axis. Proteomics of drug-resistant cell line (LC-MS/MS); RT-PCR and Western blot confirmation; siRNA knockdown of S100A16; CCK8 chemosensitivity assay; Western blot for AKT, Bcl-2, EMT markers Cancer management and research Medium 31118765
2020 S100A16 interacts with myosin-9 in response to elevated Ca²⁺ and TGF-β stimulation in renal tubular (HK-2) cells, promoting cytoskeletal reorganization (F-actin remodeling) and EMT progression during renal tubulointerstitial fibrosis. S100A16 transgenic mice subjected to unilateral ureteral obstruction (UUO) show exacerbated fibrosis compared to heterozygous knockout mice. Mass spectrometry pulldown to identify S100A16 binding partners; UUO mouse model with S100A16 transgenic and knockout mice; immunohistochemistry; Western blot for EMT and fibrosis markers; F-actin immunofluorescence in S100A16 OE/KD HK-2 cells; Ca²⁺ stimulation experiments Cell death & disease High 32094322
2020 In pancreatic ductal adenocarcinoma (PDAC), S100A16 induces EMT via enhanced expression of TWIST1 and activation of the STAT3 signaling pathway, promoting metastasis in vitro and in vivo. Combination of S100A16 downregulation with gemcitabine shows synergistic antitumor effects. In vitro knockdown/overexpression in PDAC cell lines; in vivo xenograft; Western blot for TWIST1, STAT3 activation, and EMT markers; GEO/TCGA database correlation analysis Biochemical pharmacology Medium 33359364
2021 S100A16 physically interacts with GRP78 (an ER chaperone and master regulator of ER stress) in HK-2 renal tubular cells, with colocalization occurring primarily in the ER under normal conditions. S100A16 overexpression causes GRP78 to translocate into the cytoplasm where it competes with IRE1α for GRP78 binding. Freed IRE1α becomes phosphorylated, leading to XBP1 splicing and ER stress activation. Ca²⁺ chelation with BAPTA-AM suppresses cytoplasmic colocalization of S100A16 and GRP78 and blocks downstream ER stress and fibrosis gene induction. Co-immunoprecipitation (S100A16–GRP78, competitive binding with IRE1α); immunofluorescence colocalization; Lenti-S100A16 overexpression; UUO mouse model; Western blot for ER stress markers (GRP78, p-IRE1α, XBP1s); BAPTA-AM Ca²⁺ chelation experiment Cell death & disease High 34645789
2021 S100A16 promotes pancreatic cancer cell proliferation, migration, invasion, and metastasis via AKT and ERK1/2 signaling in a fibroblast growth factor 19 (FGF19)-dependent manner. S100A16 knockdown induces G2/M cell cycle arrest and apoptosis in PDAC cells. siRNA knockdown and overexpression in PDAC cell lines; in vivo metastasis model; Western blot for AKT, ERK1/2 activation; flow cytometry for cell cycle and apoptosis; FGF19 dependency validated by rescue experiments Cell biology and toxicology Medium 33389337
2021 In gastric cancer cells, S100A16 promotes EMT, invasion, and migration via ZO-2 (Zonula Occludens-2) ubiquitination and degradation. Proteomic analysis identified ZO-2 as an S100A16 interacting protein; excessive S100A16 causes ZO-2 loss through ubiquitin-mediated degradation. Proteomic interactome analysis; co-IP; ubiquitination assay; Western blot for ZO-2, EMT markers; in vivo and in vitro proliferation and migration assays Frontiers in cell and developmental biology Medium 34650982
2021 ADAMTS19 suppresses gastric cancer cell migration and invasion by binding cytoplasmic P65 (NF-κB), reducing nuclear P65 phosphorylation, and thereby downregulating S100A16 transcription. Overexpression of S100A16 reverses the migration/invasion suppression by ADAMTS19, placing S100A16 as a direct downstream transcriptional target of the NF-κB pathway in gastric cancer. Co-immunoprecipitation (ADAMTS19–P65); immunofluorescence; dual-luciferase reporter for NF-κB/S100A16; gain- and loss-of-function assays; S100A16 rescue experiments Biomolecules Medium 33921267
2022 S100A16 promotes acute kidney injury (AKI) by activating the E3 ubiquitin ligase HRD1, which ubiquitinates and degrades the Wnt/β-catenin pathway negative regulators GSK3β and CK1α, thereby activating β-catenin signaling and inhibiting HGF secretion. S100A16 knockout in mice subjected to ischemia-reperfusion injury impeded Wnt/β-catenin activation and rescued HGF expression. S100A16 knockout mice + ischemia-reperfusion injury model; NRK-49F renal fibroblast overexpression/knockdown; Western blot for HRD1, GSK3β, CK1α, β-catenin, HGF; ubiquitination assays; ICG-001 (Wnt inhibitor) epistasis Cellular and molecular life sciences High 35279748
2022 S100A16 deficiency prevents hepatic stellate cell (HSC) activation and liver fibrosis. Mechanistically, S100A16 binds p53 protein and promotes its degradation; reduced p53 leads to increased CXCR4 expression, which activates ERK1/2 and AKT signaling to drive HSC activation. S100a16 transgenic mice develop spontaneous liver fibrosis, confirming gain-of-function pro-fibrotic activity. S100a16 knockout and transgenic mice in multiple liver fibrosis models; HSC isolation; RNA sequencing; co-IP (S100A16–p53); Western blot for CXCR4, p-ERK1/2, p-AKT; S100a16 genetic silencing in HSCs Metabolism: clinical and experimental High 35914619
2022 Downregulation of S100A16 (together with HSP27) in placenta-derived multipotent cells (PDMCs) is sufficient to drive differentiation into functional astrocytes without chemical induction. Co-silencing S100A16 and HSP27 produces cells with classical astrocytic morphology, expression of astrocyte markers, and functional electrophysiology and Ca²⁺ influx characteristics. siRNA co-silencing of S100A16 and HSP27; immunofluorescence for neural/astrocyte markers; electrophysiology; Ca²⁺ influx assay; morphology imaging Stem cell reviews and reports Medium 35061207
2024 HIF-1α transcriptionally upregulates HRD1 by binding to the HRD1 promoter (confirmed by ChIP and luciferase assay) within the S100A16-HRD1-GSK3β/CK1α signaling axis in renal hypoxia injury. The transcription factor TFAP2B was identified as a direct transcriptional activator of S100A16 (confirmed by ChIP and luciferase reporter assay), placing TFAP2B upstream of S100A16 in the hypoxic kidney injury pathway. Chromatin immunoprecipitation (ChIP) for HIF-1α at HRD1 promoter and TFAP2B at S100A16 promoter; luciferase reporter assays; S100A16 knockout rat tubular epithelial cells (NRK-52E); hypoxia/reoxygenation model; IRI mouse model; Western blot Cell death & disease High 38710691
2024 S100A16 binds to the RNA helicase MOV10 (confirmed by co-immunoprecipitation) and positively modulates MOV10 expression in lung adenocarcinoma cells. MOV10 in turn binds ITGA3 mRNA (confirmed by RNA immunoprecipitation) and stabilizes it (confirmed by actinomycin D chase assay), thereby activating ECM-receptor interaction pathways to promote LUAD malignant progression. Co-immunoprecipitation (S100A16–MOV10); RNA immunoprecipitation (MOV10–ITGA3 mRNA); actinomycin D mRNA stability assay; siRNA knockdown; Western blot; proliferation, migration, invasion, angiogenesis assays Molecular medicine reports Medium 39450567
2024 VDAC1 upregulates NF-κB/p65 signaling after myocardial ischemia/reperfusion injury, and NF-κB/p65 binds the S100A16 promoter to transcriptionally activate S100A16 expression. Elevated S100A16 then interacts with calmodulin (CaM) in a Ca²⁺-dependent manner to dysregulate the CaMKK2/AMPK pathway, contributing to cardiomyocyte apoptosis, inflammation, and ROS production. Adenovirus-mediated S100A16 inhibition reduced infarct size and improved cardiac function. Left anterior descending artery ligation/release in vivo; cardiomyocyte H/R model; Western blot for VDAC1, p-NF-κB/p65, S100A16, CaMKK2, AMPK; NF-κB/p65 promoter binding (ChIP implied); S100A16–CaM co-interaction; adenovirus-mediated S100A16 knockdown; cardiac function (echocardiography); flow cytometry for apoptosis/ROS European journal of pharmacology Medium 39613175
2024 SPDEF transcription factor enhances transcription of S100A16, which in turn activates the PI3K/AKT signaling pathway to promote pancreatic adenocarcinoma cell migration, proliferation, and invasion. S100A16 was identified as one of four key SPDEF-regulated genes by integrative genomic analysis. TCGA database mining; in vitro overexpression/knockdown; Western blot for PI3K/AKT activation; qRT-PCR; proliferation and invasion assays; SPDEF–S100A16 transcriptional correlation Biomolecules & biomedicine Low 38520747
2025 S100A16 knockdown in HeLa and SiHa cervical cancer cells inhibits migration without affecting viability. RNA sequencing revealed S100A16 transcriptionally regulates Ribophorin II (RPN2); S100A16 silencing decreases RPN2 through reduced p-STAT3, which in turn decreases p-GSK3β and prevents nuclear translocation of β-catenin, suppressing the β-catenin/TCF pathway and cell migration. S100A16 siRNA knockdown; RNA sequencing; Western blot for RPN2, p-STAT3, p-GSK3β, β-catenin; nuclear/cytosolic fractionation; cell migration assay; RPN2 overexpression rescue Biochimica et biophysica acta. Molecular cell research Medium 40907797
2025 S100A16 localizes to the nucleolus of metastatic breast cancer cells and associates with RNA Polymerase I (RPA194, the catalytic subunit of Pol I) at rDNA loci (detected by ChIP-MS). Loss of S100A16 disrupts RNA Polymerase I activation and rRNA synthesis, reverses EMT, inhibits invasion, and reduces metastatic incidence in animal models. Nucleolar proteomics from primary vs. metastatic breast cancer cell lines; ChIP-MS (S100A16 at rDNA with RPA194); S100A16 loss-of-function (siRNA/CRISPR); rRNA synthesis assay; EMT marker Western blot; invasion assay; in vivo metastasis model Cell death & disease High 40846689
2026 S100A14 stabilizes S100A16 protein through post-translational modification (not transcriptional regulation), and the S100A14/S100A16 complex reduces p53 protein stability and inhibits p53 transcriptional activity and downstream p21 expression, promoting pancreatic cancer progression. Co-IP confirmed the S100A14–S100A16 protein interaction; CHX chase assay demonstrated S100A14-dependent S100A16 protein stabilization. Co-immunoprecipitation (S100A14–S100A16); cycloheximide (CHX) chase assay for protein stability; dual-luciferase assay for p53 transcriptional activity; siRNA knockdown; Western blot for p53, p21, EMT markers; CCK-8 and Transwell assays Oncology research Medium 41799516

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2013 Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? The EMBO journal 213 23314748
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2013 Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. The Journal of allergy and clinical immunology 181 23403047
2013 Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS. Nature methods 170 23455922
2006 The DNA sequence and biological annotation of human chromosome 1. Nature 144 16710414
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2016 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling. Molecular cell 134 27591049
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2022 The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin. Nature cell biology 122 35013556
2015 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes. Molecular systems biology 120 25609649
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2011 An important role for CDK2 in G1 to S checkpoint activation and DNA damage response in human embryonic stem cells. Stem cells (Dayton, Ohio) 113 21319273
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2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
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2018 Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small-cell lung cancer cell survival in brain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 70 30183374
2006 S100A16, a novel calcium-binding protein of the EF-hand superfamily. The Journal of biological chemistry 66 17030513
2004 S100A16, a ubiquitously expressed EF-hand protein which is up-regulated in tumors. Biochemical and biophysical research communications 64 14684152
2014 Up-regulation of S100A16 expression promotes epithelial-mesenchymal transition via Notch1 pathway in breast cancer. Journal of biomedical science 47 25287362
2015 S100A16 promotes differentiation and contributes to a less aggressive tumor phenotype in oral squamous cell carcinoma. BMC cancer 46 26353754
2011 Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells. Endocrinology 46 21266506
2016 S100A16 promotes cell proliferation and metastasis via AKT and ERK cell signaling pathways in human prostate cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 44 27240591
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2021 The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis. Cell death & disease 31 34645789
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2013 S100A16 inhibits osteogenesis but stimulates adipogenesis. Molecular biology reports 31 23526364
2022 S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α. Cellular and molecular life sciences : CMLS 27 35279748
2022 S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression. Metabolism: clinical and experimental 26 35914619
2020 S100A16 suppresses the proliferation, migration and invasion of colorectal cancer cells in part via the JNK/p38 MAPK pathway. Molecular medicine reports 26 33355370
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2013 S100A14 interacts with S100A16 and regulates its expression in human cancer cells. PloS one 23 24086685
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2021 Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and Epithelial-Mesenchymal Transition Process in Gastric Cancer. Frontiers in cell and developmental biology 18 34650982
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2024 HIF-1α participates in the regulation of S100A16-HRD1-GSK3β/CK1α pathway in renal hypoxia injury. Cell death & disease 14 38710691
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2022 An inhibitor of BRD4, GNE987, inhibits the growth of glioblastoma cells by targeting C-Myc and S100A16. Cancer chemotherapy and pharmacology 13 36224471
2019 S100A16 suppresses the growth and survival of leukaemia cells and correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia. British journal of haematology 11 30916375
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2023 S100a16 Deficiency Prevents Alcohol-induced Fatty Liver Injury via Inducing MANF Expression in Mice. International journal of biological sciences 7 37928262
2023 S100A16 cooperates with DEPDC1 to promote the progression and angiogenesis of nephroblastoma through PI3K/Akt/mTOR pathway. Polish journal of pathology : official journal of the Polish Society of Pathologists 6 37955537
2021 Interference of S100A16 suppresses lipid accumulation and inflammation in high glucose-induced HK-2 cells. International urology and nephrology 6 33389513
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2022 Downregulated Calcium-Binding Protein S100A16 and HSP27 in Placenta-Derived Multipotent Cells Induce Functional Astrocyte Differentiation. Stem cell reviews and reports 4 35061207
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2024 Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer. Journal of cellular and molecular medicine 3 38924205
2024 Icariside II protects from marrow adipose tissue (MAT) expansion in estrogen-deficient mice by targeting S100A16. Journal of molecular endocrinology 3 39101576
2024 S100A16 stabilizes the ITGA3‑mediated ECM‑receptor interaction pathway to drive the malignant properties of lung adenocarcinoma cells via binding MOV10. Molecular medicine reports 3 39450567
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2024 S100A16 is a potential target for reshaping the tumor microenvironment in the hypoxic context of liver cancer. International immunopharmacology 2 38733818
2024 VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via calmodulin/CaMKK2/AMPK pathway. European journal of pharmacology 2 39613175
2024 SPDEF drives pancreatic adenocarcinoma progression via transcriptional upregulation of S100A16 and activation of the PI3K/AKT signaling pathway. Biomolecules & biomedicine 1 38520747
2026 Integrative single-cell and spatial transcriptomic reveals S100A16+ tumor endothelial cells drive angiogenesis and immunosuppression in hepatocellular carcinoma. Cancer letters 0 41722834
2026 S100A14 Facilitates Pancreatic Cancer Progression via S100A16-Mediated p53 Suppression. Oncology research 0 41799516
2026 Integrated bioinformatics and immunohistochemical analysis reveal that S100A16 is correlated with mutational burden, immune evasion, and P53 expression in gastric adenocarcinoma. International journal of clinical and experimental pathology 0 41868093
2025 Validation of S100A16 as an asthma biomarker and its role in IL-13-induced bronchial epithelial cell injury. Journal of thoracic disease 0 40688271
2025 Nucleolar proteomics identifies S100A16 as a key nucleolar protein driving breast cancer metastasis. Cell death & disease 0 40846689
2025 S100A16 knockdown reduces RPN2 expression and inhibits β-catenin/TCF signaling, leading to suppressed metastasis in cervical cancer cells. Biochimica et biophysica acta. Molecular cell research 0 40907797