Affinage

GSN

Gelsolin · UniProt P06396

Length
782 aa
Mass
85.7 kDa
Annotated
2026-06-10
37 papers in source corpus 11 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Gelsolin (GSN) is a calcium-regulated actin-remodeling protein that, through isoform-specific control of filament dynamics, governs cancer cell motility, invasion, and the epithelial-mesenchymal transition (PMID:30148861, PMID:40597347). Multiple GSN isoforms exert non-redundant functions: a secretory isoform drives invasiveness while cytosolic isoforms promote filopodia formation and 2D migration and reduce filamentous actin levels (PMID:40597347). In carcinoma cells GSN promotes invasion and metastasis through an actin-CD44-MMP chain in which GSN physically interacts with MMP14 to activate MMP2, with CD44 as a transfer node (PMID:36192574), and it reprograms cells toward a mesenchymal state by downregulating epithelial markers and upregulating mesenchymal markers (PMID:30148861). GSN mRNA stability and protein output are controlled post-transcriptionally by hnRNPK binding to the GSN 3'-UTR, an axis required for cancer cell migration (PMID:30771276). In cardiomyoblasts GSN induces hypertrophy via p38/GATA-4 signaling downstream of TGF-β and, under hypoxia, drives apoptosis by augmenting HIF-1α while suppressing p-Akt/Bcl-2 survival signaling and activating caspase-3 (PMID:24505034, PMID:27193608). Secreted/plasma gelsolin additionally inhibits Aβ-induced toxicity, with loss-of-function frameshift mutations abolishing this protection (PMID:36650038).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2014 Medium

    Established a signaling output for GSN in cardiac cells by showing it drives hypertrophy through a defined kinase-transcription factor cascade rather than acting solely as a cytoskeletal effector.

    Evidence Stable GSN overexpression in H9c2 cardiomyoblasts with p38 inhibitor and siRNA rescue, western blotting

    PMID:24505034

    Open questions at the time
    • Mechanism linking GSN to p38 activation not defined
    • Single cell-line model, no in vivo cardiac confirmation
  2. 2016 Medium

    Showed GSN can act pro-apoptotically under hypoxia, revealing a context-dependent role opposite to its anti-apoptotic activity in other settings.

    Evidence GSN overexpression and siRNA knockdown in H9c2 under hypoxia, western blotting for HIF-1α, p-Akt, Bcl-2, cleaved caspase-3

    PMID:27193608

    Open questions at the time
    • Direct molecular link between GSN and Akt/Bcl-2 regulation unresolved
    • Reconciliation with anti-apoptotic findings absent
  3. 2017 Medium

    Identified upstream regulation of GSN by the vitamin D receptor and reinforced an anti-apoptotic, neuroprotective function in a neuroinflammatory disease model.

    Evidence Lentiviral GSN overexpression in EAE, siRNA knockdown in PC12 cells, VDR gene interruption/overexpression

    PMID:28377587

    Open questions at the time
    • Whether VDR regulates GSN transcriptionally or otherwise not defined
    • Anti-apoptotic mechanism not molecularly resolved
  4. 2018 Low

    Connected GSN to EMT and autophagy programs in colorectal cancer and placed TGF-β upstream of the GSN/p38 hypertrophy axis, while characterizing isoform-ratio effects on proliferation versus invasion.

    Evidence Stable overexpression in LoVo cells, HFD aging rat serum experiments, isoform expression manipulation with invasion/proliferation assays

    PMID:30118659 PMID:30148861 PMID:30240538

    Open questions at the time
    • EMT and autophagy findings from overexpression only, no knockdown rescue
    • TGF-β epistasis inferred indirectly via serum, no direct molecular link
    • Isoform studies lack mechanistic pathway placement
  5. 2019 Medium

    Defined post-transcriptional control of GSN by hnRNPK and showed this regulation is functionally required for cancer cell migration.

    Evidence hnRNPK siRNA knockdown, 3'UTR binding assay, ectopic GSN rescue, migration assays in lung adenocarcinoma cells

    PMID:30771276

    Open questions at the time
    • Mechanism of mRNA stabilization vs translation not dissected
    • Whether other RBPs co-regulate GSN unknown
  6. 2022 Medium

    Provided a physical-interaction mechanism for GSN-driven invasion via an MMP14/CD44/MMP2 chain, moving beyond correlation to direct binding and competitive inhibition.

    Evidence Reciprocal co-immunoprecipitation, gelatinase activity assay, PEX fusion competitive inhibition, in vitro/in vivo invasion in HCC; synoviocyte secretion by ELISA

    PMID:35327525 PMID:36192574

    Open questions at the time
    • Stoichiometry and structural basis of GSN-MMP14 interaction unknown
    • How actin severing feeds into MMP activation not defined
  7. 2023 Medium

    Demonstrated a protective function of GSN against amyloid-beta toxicity that is abolished by frameshift mutations, linking GSN function to Alzheimer's disease biology.

    Evidence In vitro functional assay of mutant GSN constructs, whole genome sequencing, plasma/CSF GSN and Aβ ELISA

    PMID:36650038

    Open questions at the time
    • Molecular mechanism of Aβ toxicity inhibition not defined
    • Causality of mutations in disease onset not established
  8. 2025 Medium

    Resolved non-redundant isoform-specific roles in actin regulation and motility, and characterized immunomodulatory host-protective functions of plasma gelsolin.

    Evidence GSN-knockout melanoma cells with single-isoform rescue and actin/migration assays; murine candidemia model with pGSN injection, phagocytosis and reactive radical measurement (preprint)

    PMID:40597347

    Open questions at the time
    • Structural basis of isoform functional divergence unknown
    • pGSN immunomodulation data are from a single-lab preprint

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GSN's calcium-regulated actin-severing activity is mechanistically coupled to its diverse downstream outputs (p38/GATA-4 hypertrophy, Akt survival signaling, MMP activation, amyloid protection) across cell types remains unresolved.
  • No unifying structural or biochemical model links actin remodeling to signaling outputs
  • Isoform-specific structural determinants undefined
  • Context dependence of pro- vs anti-apoptotic roles unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005576 extracellular region 3 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 1
Partners
CD44HNRNPKMMP14

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 GSN overexpression in H9c2 cardiomyoblast cells induces cardiac hypertrophy and increases BNP expression via the p38/GATA-4 signaling pathway; pharmacological inhibition of p38 (SB203580) or GSN siRNA knockdown suppressed gelsolin-induced hypertrophy, establishing p38 and GATA-4 as downstream effectors of GSN. Stable overexpression cell lines (H9c2-GSN), siRNA knockdown, p38 inhibitor treatment, western blotting Molecular and cellular biochemistry Medium 24505034
2016 GSN overexpression in H9c2 cardiomyoblasts under hypoxia augments HIF-1α expression and reduces p-Akt and Bcl-2 survival signaling, promoting caspase-3 activation and cell death; GSN knockdown attenuated hypoxia-induced activated caspase-3 and cell death. Stable GSN overexpression cell lines, siRNA knockdown, hypoxic challenge, western blotting for HIF-1α, p-Akt, Bcl-2, cleaved caspase-3 Cell biochemistry and biophysics Medium 27193608
2017 GSN overexpression (via lentiviral injection in EAE model) delayed disease onset and reduced severity; GSN siRNA knockdown in PC12 cells confirmed its anti-apoptotic function; vitamin D-mediated downregulation of GSN was found to occur through the vitamin D receptor (VDR), as shown by VDR gene interruption and overexpression experiments. Lentiviral GSN overexpression in vivo (EAE model), siRNA knockdown in PC12 cells, VDR gene interruption/overexpression Scientific reports Medium 28377587
2019 hnRNPK binds to the 3'-UTR of GSN mRNA and positively regulates GSN mRNA and protein levels; hnRNPK knockdown reduced GSN expression and impaired cell migration in lung adenocarcinoma cells, and this migration defect was rescued by ectopic GSN expression, demonstrating that hnRNPK-driven migration is GSN-dependent. siRNA knockdown of hnRNPK, ectopic GSN expression rescue, migration assays, western blotting, 3'UTR binding assay Biological chemistry Medium 30771276
2022 GSN promotes hepatocellular carcinoma (HCC) invasion and metastasis through an actin-CD44-MMP axis: GSN interacts with MMP14 (co-immunoprecipitation) to activate MMP2, and CD44 acts as a key node in this transfer chain; competitive inhibition using MMP14 PEX fusion protein blocked CD44 binding and suppressed downstream MMP2 activation. Dual co-immunoprecipitation, immunofluorescence, western blotting, gelatinase activity assay, PEX fusion protein competitive inhibition, in vitro and in vivo invasion assays Clinical & translational oncology Medium 36192574
2018 GSN overexpression in colorectal cancer cells (LoVo) increased invasion >2-fold, downregulated epithelial markers (E-cadherin, β-catenin, claudin-1, snail) and upregulated mesenchymal markers (N-cadherin, ZEB1), indicating GSN promotes EMT; GSN overexpression also downregulated autophagy proteins ATG5-12, ATG6/BECN1, ATG7 and ATG101. Stable overexpression in LoVo cells, invasion/migration assays, western blotting for EMT and autophagy markers PloS one Low 30148861
2018 TGF-β acts as an upstream activator of GSN-dependent cardiac hypertrophy in aging rats fed a high-fat diet; exogenous TGF-β inhibited GSN-dependent hypertrophy in H9c2 cells cultured with treated serum, placing TGF-β upstream of the GSN/p38 hypertrophy axis. In vivo HFD aging rat model, H9c2 cell culture with collected serum, western blotting, Masson trichrome staining, echocardiography Environmental toxicology Low 30240538
2018 Functional characterization of an alternatively spliced GSN isoform (ASE-GSN) in head and neck squamous cell carcinoma showed that overall expression of either ASE-GSN or wild-type GSN inversely correlated with cell proliferation, while a high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion; changes in expression of either isoform caused compensatory changes in the other isoform. In vitro isoform expression manipulation, proliferation assays, invasion assays Translational research Low 30118659
2025 Three GSN isoforms (secretory A, cytosolic B, cytosolic C) are produced in melanoma cells; in GSN-knockout A375 cells restored with single isoforms: GSN-A increased invasiveness, GSN-C promoted filopodia formation and 2D migration, and both GSN-B and -C decreased filamentous actin levels, demonstrating non-redundant isoform-specific functions in actin regulation, motility, and invasion. GSN knockout cell line, single-isoform rescue expression, immunocytochemistry, migration assays, actin polymerization assays, zebrafish embryo tumor growth model Cancer cell international Medium 40597347
2025 Plasma gelsolin (pGSN) administration in a murine candidemia model reduced systemic and organ-specific inflammation, decreased blood fungal burden, prevented renal microabscess formation, enhanced phagocytic activity of human monocytes, and modulated monocyte reactive radical production (increasing nitric oxide, reducing hydrogen sulfide and ROS), demonstrating immunomodulatory and host-protective functions of secreted/plasma gelsolin. In vivo murine candidemia model with subcutaneous pGSN injection, IRDye 800CW 2-deoxyglucose imaging, histopathology, inflammatory gene expression in whole blood, phagocytosis assay, reactive radical measurement bioRxivpreprint Low
2022 Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) both produce and secrete GSN into synovial fluid, as demonstrated by isolation, culture, and ELISA of conditioned medium; GSN concentrations are significantly reduced in osteoarthritis synovial fluid compared to healthy controls. Cell isolation and culture, ELISA, western blot, immunofluorescence Biomedicines Low 35327525
2023 GSN frameshift mutations (K346fs and P3fs) result in loss of function of GSN in inhibiting Aβ-induced toxicity, as shown by in vitro experiments; plasma and CSF GSN levels are elevated in AD patients and positively correlate with CSF Aβ42, suggesting a compensatory role for GSN in countering amyloid toxicity. In vitro functional assay of mutant GSN constructs, whole genome sequencing, ELISA of plasma and CSF GSN and Aβ Journal of neurology, neurosurgery, and psychiatry Medium 36650038

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Cardiac conduction alterations in a French family with amyloidosis of the Finnish type with the p.Asp187Tyr mutation in the GSN gene. Muscle & nerve 35 16258946
2018 Opposite functions of GSN and OAS2 on colorectal cancer metastasis, mediating perineural and lymphovascular invasion, respectively. PloS one 34 30148861
2004 Genomic organization of the Neurospora crassa gsn gene: possible involvement of the STRE and HSE elements in the modulation of transcription during heat shock. Molecular genetics and genomics : MGG 22 15558319
2002 Molecular and biochemical characterization of the Neurospora crassa glycogen synthase encoded by the gsn cDNA. Molecular genetics and genomics : MGG 19 11976968
2014 Gelsolin (GSN) induces cardiomyocyte hypertrophy and BNP expression via p38 signaling and GATA-4 transcriptional factor activation. Molecular and cellular biochemistry 17 24505034
2014 Is GSN significant for hip BMD in female Caucasians? Bone 16 24607942
2016 The First Korean Family With Hereditary Gelsolin Amyloidosis Caused by p.D214Y Mutation in the GSN Gene. Annals of laboratory medicine 15 26915616
2015 Expression of Cytoplasmic 8-oxo-Gsn and MTH1 Correlates with Pathological Grading in Human Gastric Cancer. Asian Pacific journal of cancer prevention : APJCP 15 26434839
2021 Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel GSN Variant p.Glu580Lys. International journal of molecular sciences 13 33499149
2014 TGFBI, CHST6, and GSN gene analysis in Mexican patients with stromal corneal dystrophies. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 13 24801599
2020 iSOM-GSN: an integrative approach for transforming multi-omic data into gene similarity networks via self-organizing maps. Bioinformatics (Oxford, England) 12 32407457
2018 Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma. Translational research : the journal of laboratory and clinical medicine 11 30118659
2016 Hypoxia Augments Increased HIF-1α and Reduced Survival Protein p-Akt in Gelsolin (GSN)-Dependent Cardiomyoblast Cell Apoptosis. Cell biochemistry and biophysics 11 27193608
2018 The Ratio of Plasma and Urinary 8-oxo-Gsn Could Be a Novel Evaluation Index for Patients with Chronic Kidney Disease. Oxidative medicine and cellular longevity 10 29576848
2014 Full-length genome analyses of two new simian immunodeficiency virus (SIV) strains from mustached monkeys (C. Cephus) in Gabon illustrate a complex evolutionary history among the SIVmus/mon/gsn lineage. Viruses 10 25054885
2008 A systematic approach to identify STRE-binding proteins of the gsn glycogen synthase gene promoter in Neurospora crassa. Proteomics 10 18425733
2022 Production and Secretion of Gelsolin by Both Human Macrophage- and Fibroblast-like Synoviocytes and GSN Modulation in the Synovial Fluid of Patients with Various Forms of Arthritis. Biomedicines 9 35327525
2019 Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism in Neurospora crassa. Proceedings of the National Academy of Sciences of the United States of America 9 31048503
2004 Transmission disequilibrium analysis of the GSN gene in a cohort of family trios with schizophrenia. Neuroscience letters 9 15542240
2020 Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer's Disease. Frontiers in aging neuroscience 8 33192475
2017 Overexpression of GSN could decrease inflammation and apoptosis in EAE and may enhance vitamin D therapy on EAE/MS. Scientific reports 8 28377587
2017 Levels of 8-oxo-dGsn and 8-oxo-Gsn in random urine are consistent with 24 h urine in healthy subjects and patients with renal disease. Free radical research 8 28641500
2013 Cellular uptake and imaging studies of glycosylated silica nanoprobe (GSN) in human colon adenocarcinoma (HT 29 cell line). International journal of nanomedicine 8 23986637
2023 GSN gene frameshift mutations in Alzheimer's disease. Journal of neurology, neurosurgery, and psychiatry 7 36650038
2021 A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type. Human mutation 7 33973672
2023 Fusion of the High-mobility Group AT-Hook 2 (HMGA2) and the Gelsolin (GSN) Genes in Lipomas With t(9;12)(q33;q14) Chromosomal Translocation. In vivo (Athens, Greece) 6 36881074
2025 Deciphering the Immunomodulatory Function of GSN + Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis. Cell proliferation 5 40375605
2022 GSN synergies with actin-related transfer molecular chain to promote invasion and metastasis of HCC. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 5 36192574
2019 Regulation and related mechanism of GSN mRNA level by hnRNPK in lung adenocarcinoma cells. Biological chemistry 5 30771276
2018 Oral administration of alcalase potato protein hydrolysate-APPH attenuates high fat diet-induced cardiac complications via TGF-β/GSN axis in aging rats. Environmental toxicology 5 30240538
2015 Alterations of microsatellite loci GSN and D18S51 in urinary bladder cancer. Hippokratia 4 27418776
2024 Specific feature recognition on group specific networks (SFR-GSN): a biomarker identification model for cancer stages. Frontiers in genetics 3 38846963
2018 [Value of RNA oxidation product 8-oxo-Gsn in evaluating renal function in patients with chronic kidney disease]. Zhonghua yi xue za zhi 1 30440136
2026 Unraveling the matrix stiffness landscape in idiopathic pulmonary fibrosis: GSN and ARG1 as novel diagnostic biomarkers and potential therapeutic targets. International immunopharmacology 0 41671621
2026 Novel associations of GSN indel and PLAG1 c.48333G > A variants with growth traits in mature Indonesian Madura and Bali cattle. Journal of advanced veterinary and animal research 0 42226741
2025 Skin melanoma cells produce diverse gelsolin (GSN) isoforms, which play non-redundant roles in cells' proliferation and motility. Cancer cell international 0 40597347
2022 Deletions in GSN gene associated with growth traits of four Chinese cattle breeds. Molecular genetics and genomics : MGG 0 35780194

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