{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVillin (VIL1) is an epithelial cell‐specific actin‐binding protein that plays a central role in modulating actin filament dynamics. It regulates key biophysical events by bundling, capping, nucleating, and severing actin filaments in microvilli and terminal webs, thereby contributing to the maintenance of cell morphology and the epithelial‐to‐mesenchymal transition. Post‐translational modifications such as tyrosine phosphorylation decrease its binding affinity for F‐actin—shifting its activity from promoting actin polymerization to enhancing filament severing—while calcium binding further modulates its actin‐capping and depolymerizing functions. Structural mapping of its headpiece domain has delineated residues critical for bundling activity, underscoring how intrinsic biochemical regulation underpins villin’s control of cytoskeletal remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its cytoskeletal functions, villin is pivotal during dynamic cellular events such as migration and pathogen invasion. In intestinal epithelial cells, villin contributes to the remodeling of the actin cytoskeleton required for efficient membrane ruffle assembly and bacterial entry—as seen during Salmonella invasion—and for Autotaxin/LPA‐mediated cell motility. Furthermore, infections by pathogens like Giardia duodenalis trigger the degradation and redistribution of villin, adversely affecting brush border integrity, while its modulation during Helicobacter pylori exposure highlights its participation in stress‐induced reorganization. Emerging evidence even points to a potential release of villin into extracellular fluids during acute injury states, widening its physiological significance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in villin expression and localization have emerged as valuable diagnostic and prognostic markers in diverse pathological contexts. Autoantibodies against villin are highly associated with immunodysregulation syndromes (IPEX), while aberrant expression levels correlate with differentiation status and aggressiveness in several cancers—including pulmonary and cervical adenocarcinomas, hepatocellular carcinoma, esophageal squamous cell carcinoma, and certain gynecological tumors. Moreover, immunohistochemical detection of villin improves the differential diagnosis of conditions ranging from microvillus inclusion disease to distinguishing endocervical from endometrioid adenocarcinomas, thereby emphasizing its utility as a tissue‐specific biomarker."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nVillin expression is further governed by key transcriptional and signaling pathways that coordinate epithelial differentiation. Studies have reported correlations between villin mRNA levels and glycosylation profiles linked to cell differentiation in colorectal cancers, while promoter analyses have revealed that intestinal transcription factors such as Cdx2—often in collaboration with chromatin remodeling complexes—drive villin expression during the development of intestinal metaplasia and related epithelial transitions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Seema Khurana, Sudeep P George "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of cell structure and function by actin-binding proteins: villin's perspective."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2008.02.040"}], "href": "https://doi.org/10.1016/j.febslet.2008.02.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18307996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18307996"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "L Zhai, P Zhao, A Panebra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine phosphorylation of villin regulates the organization of the actin cytoskeleton."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C100418200"}], "href": "https://doi.org/10.1074/jbc.C100418200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11500485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11500485"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alok Tomar, Yaohong Wang, Narendra Kumar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of cell motility by tyrosine phosphorylated villin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e04-05-0431"}], "href": "https://doi.org/10.1091/mbc.e04-05-0431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15342783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15342783"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Narendra Kumar, Alok Tomar, Abby L Parrill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M405424200"}], "href": "https://doi.org/10.1074/jbc.M405424200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15272027"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15272027"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sudeep P George, Amin Esmaeilniakooshkghazi, Swati Roy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "F-actin-bundling sites are conserved in proteins with villin-type headpiece domains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E20-02-0158"}], "href": "https://doi.org/10.1091/mbc.E20-02-0158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32520642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32520642"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nouara Lhocine, Ellen T Arena, Perrine Bomme, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apical invasion of intestinal epithelial cells by Salmonella typhimurium requires villin to remodel the brush border actin cytoskeleton."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2014.12.003"}], "href": "https://doi.org/10.1016/j.chom.2014.12.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25600187"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25600187"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Swati Roy, Amin Esmaeilniakooshkghazi, Srinivas Patnaik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2017.12.016"}], "href": "https://doi.org/10.1053/j.gastro.2017.12.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29274870"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29274870"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Amol Bhargava, James A Cotton, Brent R Dixon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Giardia duodenalis Surface Cysteine Proteases Induce Cleavage of the Intestinal Epithelial Cytoskeletal Protein Villin via Myosin Light Chain Kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0136102"}], "href": "https://doi.org/10.1371/journal.pone.0136102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26334299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26334299"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Seema Khurana, Alok Tomar, Sudeep P George, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2007.10.028"}], "href": "https://doi.org/10.1016/j.yexcr.2007.10.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18054784"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18054784"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Qiuping Li, Yanmei Zhu, Jun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HpSlyD inducing CDX2 and VIL1 expression mediated through TCTP protein may contribute to intestinal metaplasia in the stomach."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-02642-y"}], "href": "https://doi.org/10.1038/s41598-017-02642-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28536478"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28536478"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jean-Paul Decuypere, Laurens J Ceulemans, Tine Wylin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasmatic Villin 1 Is a Novel In Vivo Marker of Proximal Tubular Cell Injury During Renal Ischemia-Reperfusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transplantation (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/TP.0000000000001876"}], "href": "https://doi.org/10.1097/TP.0000000000001876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28704336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28704336"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Vito Lampasona, Laura Passerini, Federica Barzaghi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0078664"}], "href": "https://doi.org/10.1371/journal.pone.0078664"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24250806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24250806"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ichiro Kobayashi, Mitsuru Kubota, Masafumi Yamada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autoantibodies to villin occur frequently in IPEX, a severe immune dysregulation, syndrome caused by mutation of FOXP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clim.2011.05.010"}], "href": "https://doi.org/10.1016/j.clim.2011.05.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21741320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21741320"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Muhammad F Bari, Helen Brown, Andrew G Nicholson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histopathology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/his.12278"}], "href": "https://doi.org/10.1111/his.12278"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24266897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24266897"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Long Zhao, Shanshan Huang, Jinjun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinicopathological, radiographic, and oncogenic features of primary pulmonary enteric adenocarcinoma in comparison with invasive adenocarcinoma in resection specimens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000008153"}], "href": "https://doi.org/10.1097/MD.0000000000008153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28953659"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28953659"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Céline Revenu, Matthieu Courtois, Alphée Michelot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Villin severing activity enhances actin-based motility in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e06-05-0423"}], "href": "https://doi.org/10.1091/mbc.e06-05-0423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17182858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17182858"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Maimaiti Xieraili, Mahmut Yasen, Kaoru Mogushi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Villin 1 is a predictive factor for the recurrence of high serum alpha-fetoprotein-associated hepatocellular carcinoma after hepatectomy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1349-7006.2012.02315.x"}], "href": "https://doi.org/10.1111/j.1349-7006.2012.02315.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22530999"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22530999"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Junfen Xu, Jian Zou, Luyao Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptome analysis uncovers the diagnostic value of miR-192-5p/HNF1A-AS1/VIL1 panel in cervical adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-73523-0"}], "href": "https://doi.org/10.1038/s41598-020-73523-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33024199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33024199"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Nick M Shillingford, Monica L Calicchio, Lisa A Teot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Villin immunohistochemistry is a reliable method for diagnosing microvillus inclusion disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Surg Pathol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/PAS.0000000000000355"}], "href": "https://doi.org/10.1097/PAS.0000000000000355"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25517957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25517957"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Zhang-Mei Peng, Wei Yu, Ying Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A four actin-binding protein signature model for poor prognosis of patients with esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25337239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25337239"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Etsuko Nakamura, Toyomi Satoh, Mayumi Iwakawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Villin1, a diagnostic marker for endometrial adenocarcinoma with high grade nuclear atypia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.12.3.15964"}], "href": "https://doi.org/10.4161/cbt.12.3.15964"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21623163"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21623163"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Mariem Elfeky, Ola Harb, Loay Gertallah "}, {"type": "b", "children": [{"type": "t", "text": "Panel of Villin, Pro-Ex-C, Estrogen Receptor and Progesterone Receptor Expressions Could Help in Differentiation Between Endocervical and Endometrioid Adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Turk Patoloji Derg (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5146/tjpath.2017.01399"}], "href": "https://doi.org/10.5146/tjpath.2017.01399"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28832070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28832070"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Stephanie Holst, Anna J M Deuss, Gabi W van Pelt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "N-glycosylation Profiling of Colorectal Cancer Cell Lines Reveals Association of Fucosylation with Differentiation and Caudal Type Homebox 1 (CDX1)/Villin mRNA Expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Proteomics (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/mcp.M115.051235"}], "href": "https://doi.org/10.1074/mcp.M115.051235"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26537799"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26537799"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Nobutake Yamamichi, Ken-ichi Inada, Chihiro Furukawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2009.01.006"}], "href": "https://doi.org/10.1016/j.yexcr.2009.01.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19371634"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19371634"}]}]}]}