Affinage

TWF1

Twinfilin-1 · UniProt Q12792

Length
350 aa
Mass
40.3 kDa
Annotated
2026-06-10
100 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TWF1 (twinfilin 1) is an actin-binding protein that functions as a downstream effector promoting epithelial-to-mesenchymal transition (EMT) and chemotherapy resistance across multiple carcinoma contexts (PMID:23340433, PMID:35697274). Its expression is held in check post-transcriptionally by microRNAs that bind its 3'UTR: miR-30c in breast cancer (PMID:23340433) and miR-30a/c-5p in clear cell renal cell carcinoma, where direct binding was confirmed by luciferase reporter assay (PMID:35697274). When this repression is relieved, elevated TWF1 drives a mesenchymal program—knockdown of TWF1 reduces migration, invasion, and EMT-marker expression while restoring epithelial markers Claudin-1 and ZO-1 (PMID:35697274). In breast cancer, miR-30c is itself transcriptionally controlled by GATA3, and IL-11 acts as a secondary downstream target of the miR-30c–TWF1 axis (PMID:23340433). The biochemical mechanism by which the TWF1 protein itself executes EMT and chemoresistance has not been characterized in the available corpus; the evidence establishes TWF1 as a regulated node in these phenotypes rather than defining its molecular action.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2013 Medium

    Established TWF1 as a functionally relevant, microRNA-regulated driver of cancer phenotype by showing it is a direct miR-30c target whose suppression promotes EMT and chemoresistance.

    Evidence miR-30c overexpression/knockdown with EMT and chemoresistance functional assays in breast cancer cells; GATA3 shown to regulate miR-30c and IL-11 identified as a downstream target

    PMID:23340433

    Open questions at the time
    • How the TWF1 protein biochemically promotes EMT was not resolved
    • Direct 3'UTR binding not demonstrated by reporter assay in this study
    • Link between TWF1 actin-binding activity and the EMT phenotype unestablished
  2. 2019 Low

    Extended TWF1 regulation to a ceRNA framework in drug-resistant pancreatic cancer, positioning lncRNA SBF2-AS1 as an upstream de-repressor of TWF1 via miR-142-3p sponging.

    Evidence Luciferase reporter and RIP assays for SBF2-AS1/miR-142-3p and miR-142-3p/TWF1; knockdown/overexpression in gemcitabine-resistant cell lines

    PMID:31619579

    Open questions at the time
    • Single-lab ceRNA axis; TWF1 protein mechanism not directly studied
    • Whether TWF1 alone is sufficient to confer gemcitabine resistance not isolated
  3. 2021 Low

    Generalized the lncRNA-sponging mode of TWF1 upregulation to cisplatin-resistant hepatocellular carcinoma, linking TWF1 levels to drug resistance, invasion, and apoptosis suppression.

    Evidence Luciferase reporter and RIP for FGD5-AS1/miR-153-3p and miR-153-3p/TWF1; siRNA knockdown with CCK-8, colony formation, Transwell, and TUNEL assays

    PMID:34519634

    Open questions at the time
    • Single-lab ceRNA axis; biochemical role of TWF1 protein not resolved
    • Mechanism connecting TWF1 to apoptosis regulation unknown
  4. 2022 Medium

    Confirmed direct 3'UTR targeting of TWF1 by miR-30a/c-5p and demonstrated that loss of TWF1 reverses the mesenchymal program in renal cancer, solidifying TWF1 as an EMT effector.

    Evidence Luciferase reporter assay for miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown with migration/invasion and EMT-marker assays plus patient-tissue immunohistochemistry in ccRCC

    PMID:35697274

    Open questions at the time
    • Molecular mechanism by which TWF1 modulates Claudin-1/ZO-1 and EMT not defined
    • Connection between TWF1 actin-binding function and EMT signaling unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which TWF1 protein executes EMT and chemoresistance—its actin-related activity, binding partners, and the signaling steps linking it to epithelial-marker loss—remains unresolved.
  • No structural or enzymatic characterization of TWF1 in the corpus
  • No identified protein partners or actin-regulatory mechanism tied to the EMT phenotype
  • Whether TWF1's actin-binding activity is required for chemoresistance is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2
Pathway
R-HSA-1643685 Disease 2

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 TWF1 (twinfilin 1), an actin-binding protein, is a direct target of microRNA-30c in breast cancer cells; miR-30c suppression of TWF1 promotes epithelial-to-mesenchymal transition and chemotherapy resistance, and IL-11 was identified as a secondary downstream target of this pathway. Direct targeting validated by miRNA overexpression/knockdown, functional assays for EMT and chemoresistance, with miR-30c shown to be transcriptionally regulated by GATA3 Nature communications Medium 23340433
2022 TWF1 (twinfilin actin binding protein 1) is a direct target of miR-30a/c-5p in clear cell renal cell carcinoma (ccRCC); both miRs directly bind TWF1 3'UTR (confirmed by luciferase assay), and TWF1 knockdown reduced cell aggressiveness and EMT markers while upregulating epithelial markers Claudin-1 and ZO-1, implicating TWF1 in EMT regulation. Luciferase reporter assay confirming direct miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown of TWF1 with functional assays (migration, invasion, EMT marker expression); immunohistochemistry in patient tissues Translational research : the journal of laboratory and clinical medicine Medium 35697274
2019 TWF1 expression is regulated by the lncRNA SBF2-AS1/miR-142-3p axis in gemcitabine-resistant pancreatic cancer: SBF2-AS1 acts as a ceRNA to sponge miR-142-3p, thereby relieving miR-142-3p-mediated repression of TWF1 and promoting drug resistance and EMT. Luciferase reporter and RNA immunoprecipitation (RIP) assays confirming SBF2-AS1 binding to miR-142-3p and miR-142-3p targeting of TWF1; knockdown/overexpression functional assays in gemcitabine-resistant cell lines Aging Low 31619579
2021 TWF1 expression is regulated by the lncRNA FGD5-AS1/miR-153-3p axis in cisplatin-resistant hepatocellular carcinoma: FGD5-AS1 sponges miR-153-3p to upregulate TWF1, and TWF1 knockdown reduced drug resistance, invasion, and promoted apoptosis in HCC cells. Luciferase reporter and RIP assays confirming FGD5-AS1/miR-153-3p and miR-153-3p/TWF1 interactions; siRNA knockdown of TWF1 with CCK-8, colony formation, Transwell, and TUNEL functional assays Bioengineered Low 34519634

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nature communications 207 23340433
2014 Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Molecular cell 205 24508390
2016 Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. The Journal of clinical investigation 185 27701147
2011 An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC infectious diseases 150 22168544
2017 Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair. Nature communications 134 29158488
2012 Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PloS one 132 23272213
2012 Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats. The Journal of comparative neurology 129 22173709
2014 Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair. Proceedings of the National Academy of Sciences of the United States of America 124 24717843
2013 Emergence, circulation, and spatiotemporal phylogenetic analysis of coxsackievirus a6- and coxsackievirus a10-associated hand, foot, and mouth disease infections from 2008 to 2012 in Shenzhen, China. Journal of clinical microbiology 114 23966496
1997 Characterization of early aldosterone-induced RNAs identified in A6 kidney epithelia. Pflugers Archiv : European journal of physiology 112 9178633
2007 Annexin A6-induced alterations in cholesterol transport and caveolin export from the Golgi complex. Traffic (Copenhagen, Denmark) 100 17822395
2010 Annexin A6-Linking Ca(2+) signaling with cholesterol transport. Biochimica et biophysica acta 87 20888375
2004 Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 14749437
2005 Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene 84 15940262
2017 Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody. Nature communications 79 28894095
2015 Role of annexin A6 in cancer. Oncology letters 79 26622779
2000 Aldosterone induces ras methylation in A6 epithelia. American journal of physiology. Cell physiology 79 10913010
1986 Activators of protein kinase C inhibit sodium transport in A6 epithelia. The American journal of physiology 79 2420202
1994 Arginine vasopressin and forskolin regulate apical cell surface expression of epithelial Na+ channels in A6 cells. The American journal of physiology 71 8160801
2012 Annexin A6 is a scaffold for PKCα to promote EGFR inactivation. Oncogene 68 22797061
2011 Human annexin A6 interacts with influenza a virus protein M2 and negatively modulates infection. Journal of virology 68 22114333
2008 Annexin A6 inhibits Ras signalling in breast cancer cells. Oncogene 65 18850003
2018 Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor. PLoS pathogens 64 29522575
2010 Annexin A6-regulator of the EGFR/Ras signalling pathway and cholesterol homeostasis. The international journal of biochemistry & cell biology 64 20044025
2019 Recombinant annexin A6 promotes membrane repair and protects against muscle injury. The Journal of clinical investigation 61 31545299
2016 Characterization of Coxsackievirus A6- and Enterovirus 71-Associated Hand Foot and Mouth Disease in Beijing, China, from 2013 to 2015. Frontiers in microbiology 61 27065963
2009 Plasma membrane-associated annexin A6 reduces Ca2+ entry by stabilizing the cortical actin cytoskeleton. The Journal of biological chemistry 60 19386597
2017 Annexin A6-A multifunctional scaffold in cell motility. Cell adhesion & migration 59 28060548
2011 A6 peptide activates CD44 adhesive activity, induces FAK and MEK phosphorylation, and inhibits the migration and metastasis of CD44-expressing cells. Molecular cancer therapeutics 57 21885863
2002 Hypotonic induction of SGK1 and Na+ transport in A6 cells. American journal of physiology. Renal physiology 56 12060592
2016 Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin. Journal of cellular biochemistry 55 26239765
2011 Annexin A6 is an organizer of membrane microdomains to regulate receptor localization and signalling. IUBMB life 53 21990038
2021 Exosomal annexin A6 induces gemcitabine resistance by inhibiting ubiquitination and degradation of EGFR in triple-negative breast cancer. Cell death & disease 50 34238922
2013 Annexin A6-balanced late endosomal cholesterol controls influenza A replication and propagation. mBio 50 24194536
2006 Molecular mechanisms involved in Ras inactivation: the annexin A6-p120GAP complex. BioEssays : news and reviews in molecular, cellular and developmental biology 50 17120209
1987 Energy metabolism of renal cell lines, A6 and MDCK: regulation by Na-K-ATPase. The American journal of physiology 49 3030121
2019 Long non-coding SBF2-AS1 acting as a competing endogenous RNA to sponge microRNA-142-3p to participate in gemcitabine resistance in pancreatic cancer via upregulating TWF1. Aging 48 31619579
2015 Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration. The Journal of biological chemistry 48 26578516
2015 Modulation of CD44 Activity by A6-Peptide. Frontiers in immunology 45 25870596
2015 S100 calcium-binding protein A6 promotes epithelial-mesenchymal transition through β-catenin in pancreatic cancer cell line. PloS one 44 25799022
2013 Annexin A6 interacts with p65 and stimulates NF-κB activity and catabolic events in articular chondrocytes. Arthritis and rheumatism 43 24022118
2018 Coxsackievirus A6 Induces Cell Cycle Arrest in G0/G1 Phase for Viral Production. Frontiers in cellular and infection microbiology 42 30159255
2016 Annexin A6 in the liver: From the endocytic compartment to cellular physiology. Biochimica et biophysica acta. Molecular cell research 42 27984093
2015 Evidence for annexin A6-dependent plasma membrane remodelling of lipid domains. British journal of pharmacology 41 25409976
2007 Intracellular calcium plays a role as the second messenger of hypotonic stress in gene regulation of SGK1 and ENaC in renal epithelial A6 cells. American journal of physiology. Renal physiology 39 17959754
2018 The immunogenicity and protection effect of an inactivated coxsackievirus A6, A10, and A16 vaccine against hand, foot, and mouth disease. Vaccine 38 29739716
2008 Interaction between S100A8/A9 and annexin A6 is involved in the calcium-induced cell surface exposition of S100A8/A9. The Journal of biological chemistry 38 18786929
2023 Annexin A6 mediates calcium-dependent exosome secretion during plasma membrane repair. eLife 37 37204294
2016 Molecular epidemiology and the evolution of human coxsackievirus A6. The Journal of general virology 36 27692044
2016 Annexin A6 regulates interleukin-2-mediated T-cell proliferation. Immunology and cell biology 34 26853809
2015 Prevalence of Coxsackievirus A6 and Enterovirus 71 in Hand, Foot and Mouth Disease in Nanjing, China in 2013. The Pediatric infectious disease journal 34 26090576
2008 Learning and memory impairment in Eph receptor A6 knockout mice. Neuroscience letters 34 18450376
2010 Deficiency of annexins A5 and A6 induces complex changes in the transcriptome of growth plate cartilage but does not inhibit the induction of mineralization. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 19580468
2005 Inhibition of H-Ras and MAPK is compensated by PKC-dependent pathways in annexin A6 expressing cells. Cellular signalling 33 16183252
2020 Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice. Hepatology (Baltimore, Md.) 32 32170749
2013 Diversity of the human LILRB3/A6 locus encoding a myeloid inhibitory and activating receptor pair. Immunogenetics 32 24096970
2020 Annexin-A6 in Membrane Repair of Human Skeletal Muscle Cell: A Role in the Cap Subdomain. Cells 31 32708200
2018 Divergent Pathogenic Properties of Circulating Coxsackievirus A6 Associated with Emerging Hand, Foot, and Mouth Disease. Journal of virology 31 29563294
2009 Gradients of Eph-A6 expression in primate retina suggest roles in both vascular and axon guidance. Molecular vision 31 20011078
2020 Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs. Viruses 30 32752001
1994 Basolateral potassium membrane permeability of A6 cells and cell volume regulation. The Journal of membrane biology 30 7516437
1989 Aldosterone receptors in A6 cells: physicochemical characterization and autoradiographic study. The American journal of physiology 30 2529773
2012 Intracellular modulation of signaling pathways by annexin A6 regulates terminal differentiation of chondrocytes. The Journal of biological chemistry 29 22399299
2000 Activation of A(3) adenosine receptor induces calcium entry and chloride secretion in A(6) cells. The Journal of membrane biology 28 11083899
2005 Hydrogen peroxide and epidermal growth factor activate phosphatidylinositol 3-kinase and increase sodium transport in A6 cell monolayers. American journal of physiology. Renal physiology 27 15671346
2021 Origin and evolution of HIV-1 subtype A6. PloS one 26 34898626
2020 Binding specificity of ostreolysin A6 towards Sf9 insect cell lipids. Biochimica et biophysica acta. Biomembranes 24 32298680
2016 Annexin A6 protein is downregulated in human hepatocellular carcinoma. Molecular and cellular biochemistry 24 27334756
2022 Anti-inflammatory effect of Bifidobacterium animalis subsp. lactis A6 on DSS-induced colitis in mice. Journal of applied microbiology 23 35737740
2022 Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine. Antimicrobial agents and chemotherapy 22 34978890
2021 Characterization of Coxsackievirus A6 Strains Isolated From Children With Hand, Foot, and Mouth Disease. Frontiers in cellular and infection microbiology 22 34490141
2016 Annexin A6 regulates adipocyte lipid storage and adiponectin release. Molecular and cellular endocrinology 22 27702590
2012 Functional expression of amylosucrase, a glucan-synthesizing enzyme, from Arthrobacter chlorophenolicus A6. Journal of microbiology and biotechnology 22 22814500
1997 Cloning and functional expression of a ClC Cl- channel from the renal cell line A6. The American journal of physiology 22 9357761
2021 Efficacy of a coxsackievirus A6 vaccine candidate in an actively immunized mouse model. Emerging microbes & infections 21 33739899
2011 Interaction of annexin A6 with alpha actinin in cardiomyocytes. BMC cell biology 21 21272378
1996 Rapamycin inhibits protein kinase C activity and stimulates Na+ transport in A6 cells. The Journal of biological chemistry 21 8943313
2022 A conserved annexin A6-mediated membrane repair mechanism in muscle, heart, and nerve. JCI insight 20 35866481
2017 Impact of Coxsackievirus A6 emergence on hand, foot, and mouth disease epidemic in Osaka City, Japan. Journal of medical virology 20 28771766
2023 Annexin A1, A2, A5, and A6 involvement in human pathologies. Proteins 19 37218507
2010 Carboxypeptidase A6 in zebrafish development and implications for VIth cranial nerve pathfinding. PloS one 19 20885977
2005 Identification and distribution of mouse carboxypeptidase A-6. Brain research. Molecular brain research 19 15950771
2024 Evolutionary Diversity of Coxsackievirus A6 Causing Severe Hand, Foot, and Mouth Disease - China, 2012-2023. China CDC weekly 18 38846357
2001 Naloxone inhibits A6 cell Na(+)/H(+) exchange by activating protein kinase C via the mobilization of intracellular calcium. Experimental nephrology 18 11549852
2021 Long non-coding RNA FGD5-AS1 contributes to cisplatin resistance in hepatocellular carcinoma via sponging microRNA-153-3p by upregulating Twinfilin Actin Binding Protein 1 (TWF1). Bioengineered 17 34519634
2020 Annexin A6 improves anti-migratory and anti-invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells. The FEBS journal 17 31869496
2012 Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy. The Journal of biological chemistry 17 23105115
2024 Evolution, recombination and geographic spreading of global Coxsackievirus A6. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 16 38749308
2022 Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions. Scientific reports 16 35022465
2018 Inhibition of somatosensory mechanotransduction by annexin A6. Science signaling 16 29921656
2018 Molecular epidemiology of coxsackievirus A6 derived from hand, foot, and mouth disease in Fukuoka between 2013 and 2017. Journal of medical virology 16 29981169
2015 Novel carboxypeptidase A6 (CPA6) mutations identified in patients with juvenile myoclonic and generalized epilepsy. PloS one 16 25875328
1992 Na+ transport and impedance properties of cultured renal (A6 and 2F3) epithelia. The Journal of membrane biology 16 1556737
2019 Hand-foot-and-mouth disease in uruguay: Coxsackievirus A6 identified as causative of an outbreak in a rural childcare center. Journal of medical virology 15 31502682
2002 The increase in the frequency of MICA gene A6 allele in oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 15 12190814
1994 A monoclonal antibody (A6) recognizing a unique epitope restricted to CD45RO and RB isoforms of the leukocyte common antigen family identifies functional T cell subsets. Cellular immunology 15 7522974
2024 Defluorination of PFAS by Acidimicrobium sp. strain A6 and potential applications for remediation. Methods in enzymology 14 38658084
2022 Epigenetically-regulated miR-30a/c-5p directly target TWF1 and hamper ccRCC cell aggressiveness. Translational research : the journal of laboratory and clinical medicine 14 35697274
2020 Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets. PloS one 14 32298357
2019 Tyrosine kinase Eph receptor A6 sensitizes glioma-initiating cells towards bone morphogenetic protein-induced apoptosis. Cancer science 14 31483918

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