Tumor suppressor scribble regulates assembly of tight junctions in the intestinal epithelium
Open accessAbstract
Formation of the epithelial barrier and apico-basal cell polarity represent two characteristics and mutually dependent features of differentiated epithelial monolayers. They are controlled by special adhesive structures, tight junctions (TJs), and polarity protein complexes that define the apical and the basolateral plasma membrane. The functional interplay between TJs and polarity complexes remains poorly understood. We investigated the role of Scribble, a basolateral polarity protein and known tumor suppressor, in regulating TJs in human intestinal epithelium. Scribble was enriched at TJs in T84 and SK-CO15 intestinal epithelial cell monolayers and sections of normal human colonic mucosa. siRNA-mediated knockdown of Scribble in SK-CO15 cells attenuated development of epithelial barrier and inhibited TJ reassembly independently of other basolateral polarity proteins Lgl-1 and Dlg-1. Scribble selectively co-imunoprecipitated with TJ protein ZO-1, and ZO-1 was important for Scribble recruitment to intercellular junctions and TJ reassembly. Lastly, Scribble was mislocalized from TJs and its expression down-regulated in interferon-gamma-treated T84 cell monolayers and inflamed human intestinal mucosa in vivo. We conclude that Scribble is an important regulator of TJ functions and plasticity in the intestinal epithelium. Down-regulation of Scribble may mediate mucosal barrier breakdown during intestinal inflammation.
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Many Scribble binding partners localizing to adherens or tight junctions have been identified, some by coimmunoprecipitation in a complex with intact Scribble protein, and others for which the interaction is direct and maps to the PDZ domains.
“Many Scribble binding partners localizing to adherens or tight junctions have been identified, some by coimmunoprecipitation in a complex with the intact Scribble protein (e.g., ZO-1 or DLG5; Ivanov et al., 2010; Liu et al., 2017), and others for which the interaction is direct and maps to the PDZ domains (e.g., β-catenin, the Rho GAP DLC3; Ivarsson et al., 2014; Hendrick et al., 2016).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Ivanov et al., 2010
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References 69 · Cited by 73
- Authors
- Ivanov, A. I., Young, C., Beste, K. D., Capaldo, C. T., Humbert, P. O., Brennwald, P., Parkos, C. A., & Nusrat, A.
- Affiliations
- University of Rochester Medicine (US)
- Emory University (US)
- Peter MacCallum Cancer Centre (AU)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Ivanov, Andrei I.
- Nusrat, Asma
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 176
- Issue
- 1
- Pages
- 134-145
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2797876
- OpenAlex
- W2090919838
- Cited by
- 73
- References
- 69
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 9 · 2012: 12
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (DK 55679, R24DK 064399, DK 61379, DK 72564)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- Scribble, tight junctions, intestinal epithelium, epithelial barrier function, apical-basal polarity, ZO-1, tumor suppressor, intestinal inflammation, interferon-gamma, DLG1
- MeSH terms
- Discs Large Homolog 1 Protein, Animals, Cell Line, Epithelial Cells, Humans, Inflammation, Interferon-gamma, Intestinal Mucosa, Membrane Proteins, Phosphoproteins, Protein Binding, Down-Regulation, Tight Junctions, Gene Silencing, Tumor Suppressor Proteins, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Mice, Zonula Occludens-1 Protein
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