Qin, Y. , Capaldo, C. , Gumbiner, B.M. & Macara, I.G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061-1071

Department of Cell Biology, University of Virginia, Charlottesville, Virginia, United States
The Journal of Cell Biology (Impact Factor: 9.83). 01/2006; 171(6):1061-71. DOI: 10.1083/jcb.200506094
Source: PubMed


Scribble (Scrib) is a conserved polarity protein required in Drosophila melanogaster for synaptic function, neuroblast differentiation, and epithelial polarization. It is also a tumor suppressor. In rodents, Scrib has been implicated in receptor recycling and planar polarity but not in apical/basal polarity. We now show that knockdown of Scrib disrupts adhesion between Madin-Darby canine kidney epithelial cells. As a consequence, the cells acquire a mesenchymal appearance, migrate more rapidly, and lose directionality. Although tight junction assembly is delayed, confluent monolayers remain polarized. These effects are independent of Rac activation or Scrib binding to betaPIX. Rather, Scrib depletion disrupts E-cadherin-mediated cell-cell adhesion. The changes in morphology and migration are phenocopied by E-cadherin knockdown. Adhesion is partially rescued by expression of an E-cadherin-alpha-catenin fusion protein but not by E-cadherin-green fluorescent protein. These results suggest that Scrib stabilizes the coupling between E-cadherin and the catenins and are consistent with the idea that mammalian Scrib could behave as a tumor suppressor by regulating epithelial cell adhesion and migration.

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    • "Binding of neurons to N - cadherin extracellular domain - Fc ( NcadECD - Fc ) fusion protein ( mouse ) ( R&D Systerms # 6626 - NC - 050 ) was done as previously described ( Qin et al . , 2005 ) ."
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    ABSTRACT: Proper brain function depends on correct neuronal migration during development, which is known to be regulated by cytoskeletal dynamics and cell-cell adhesion. Myosin X (Myo10), an uncharacteristic member of the myosin family, is an important regulator of cytoskeleton that modulates cell motilities in many different cellular contexts. We previously reported that Myo10 was required for neuronal migration in the developing cerebral cortex, but the underlying mechanism was still largely unknown. Here, we found that knockdown of Myo10 expression disturbed the adherence of migrating neurons to radial glial fibers through abolishing surface Neuronal cadherin (N-cadherin) expression, thereby impaired neuronal migration in the developmental cortex. Next, we found Myo10 interacted with N-cadherin cellular domain through its FERM domain. Furthermore, we found knockdown of Myo10 disrupted N-cadherin subcellular distribution and led to localization of N-cadherin into Golgi apparatus and endosomal sorting vesicle. Taking together, these results reveal a novel mechanism of Myo10 interacting with N-cadherin and regulating its cell-surface expression, which is required for neuronal adhesion and migration.
    Full-text · Article · Sep 2015 · Frontiers in Cellular Neuroscience
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    • "Scrib localization at the basolateral membrane is dependent on cell–cell adhesion mediated by E-cadherin.28 In return, the Scrib complex is necessary to maintain E-cadherin-mediated adhesions, and specifies the basolateral membrane.29 Furthermore the Scrib complex opposes apical membrane identity and in Drosophila, expression of Scrib mutants cause the delocalization of apical proteins to all cell surfaces.30 "
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    ABSTRACT: Breast cancer is a heterogeneous group of diseases that frequently exhibits loss of growth control, and disrupted tissue organization and differentiation. Several recent studies indicate that apical-basal polarity provides a tumor-suppressive function, and that disrupting polarity proteins affects many stages of breast cancer progression from initiation through metastasis. In this review we highlight some of the recent advances in our understanding of the molecular mechanisms by which loss of apical-basal polarity deregulates apoptosis, proliferation, and promotes invasion and metastasis in breast cancer.
    Full-text · Article · Jan 2014 · Breast Cancer: Targets and Therapy
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    • "scrib has been shown to act as a neoplastic tumor suppressor (Bilder, 2004; Bilder et al., 2000; Bilder and Perrimon, 2000) and scrib-deficient follicular cells exhibit mislocalization of basolateral junction proteins such as E-cadherin (Zhao et al., 2008). Scrib-depleted MDCK cells were less adherent apparently due to compromised E-cadherin function (Qin et al., 2005). Analysis of the mouse mutant, Crc, which expresses a truncated form of Scrib in which the last two PDZ domains are absent (Murdoch et al., 2003), has shown that Scrib is essential for planar cell polarity (Montcouquiol et al., 2003), for maintaining epithelial cohesion during lung development (Yates et al., 2013) and for angiogenesis (Michaelis et al., 2013). "
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    ABSTRACT: The integrity and function of epithelial tissues depends on the establishment and maintenance of defining characteristics of epithelial cells, cell-cell adhesion and cell polarity. Disruption of these characteristics can lead to the loss of epithelial identity through a process called epithelial to mesenchymal transition (EMT), which can contribute to pathological conditions such as tissue fibrosis and invasive cancer. In invertebrates, the epithelial polarity gene scrib plays a critical role in establishing and maintaining cell adhesion and polarity. In this study we asked if the mouse homolog, Scrib, is required for establishment and/or maintenance of epithelial identity in vivo. To do so, we conditionally deleted Scrib in the head ectoderm tissue that gives rise to both the ocular lens and the corneal epithelium. Deletion of Scrib in the lens resulted in a change in epithelial cell shape from cuboidal to flattened and elongated. Early in the process, the cell adhesion protein, E-cadherin, and apical polarity protein, ZO-1, were downregulated and the myofibroblast protein, αSMA, was upregulated, suggesting EMT was occurring in the Scrib deficient lenses. Correlating temporally with the upregulation of αSMA, Smad3 and Smad4, TGFβ signaling intermediates, accumulated in the nucleus and Snail, a TGFβ target and transcriptional repressor of the gene encoding E-cadherin, was upregulated. Pax6, a lens epithelial transcription factor required to maintain lens epithelial cell identity also was downregulated. Loss of Scrib in the corneal epithelium also led to molecular changes consistent with EMT, suggesting that the effect of Scrib deficiency was not unique to the lens. Together, these data indicate that mammalian Scrib is required to maintain epithelial identity and that loss of Scrib can culminate in EMT, mediated, at least in part, through TGFβ signaling.
    Full-text · Article · Oct 2013 · Developmental Biology
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