Article

The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin

Center for Cell Signaling, Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 01/2006; 171(6):1061-71. DOI: 10.1083/jcb.200506094
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest Proteins found in cells often have more than one role. Scribble is one such multi-tasking protein that is found in a diverse range of species, including fruit flies and humans. Although Scribble commonly helps to ensure that the components of a cell are in their correct locations, its exact roles vary between species. To perform its role well, Scribble itself must localize to the cell cortex—the inside surface of the cell membrane—at the regions where cells connect to one another. How this localization occurs is not fully understood; and defects in the human form of Scribble have been linked to diseases including spina bifida and cancer. Much of the Scribble protein is very similar across different species, but the fruit fly and human version of the protein have large differences in their ‘C-terminal region’ that makes up one end of each protein. Boëda and Etienne-Manneville now show that in humans and other animals with backbones—but not in fruit flies—the C-terminal region of Scribble contains three repeats of a sequence called the SADH motif. These motifs can bind to proteins called beta spectrins, which connect the cell's outer membrane to the scaffolding-like structure inside the cell that provides support. Mutations that alter the SADH motif interfere with Scribble's ability to bind to the scaffolding, and alters Scribble localization at cell–cell contacts or the cell cortex. Boëda and Etienne-Manneville also found that some mutations linked to spina bifida and cancer affect the SADH motif, suggesting that this motif has a wider role in disease. While the abnormal localization of Scribble inside cells is frequently observed in particularly difficult to survive cancers, the molecular mechanism that causes Scribble to fail to localize to the cell periphery is still poorly understood. Boëda and Etienne-Manneville's work establishes the beta spectrin family of proteins as regulators that stabilize Scribble at the cell cortex and suggests that Scribble-associated diseases might depend on the integrity of the spectrin network. DOI: http://dx.doi.org/10.7554/eLife.04726.002
    eLife Sciences 02/2015; 4. DOI:10.7554/eLife.04726 · 8.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The structure and function of the barrier layers restricting the free diffusion of substances between the central nervous system (brain and spinal cord) and the systemic circulation is of great medical interest as various pathological conditions often lead to their impairment. Excessive leakage of blood-borne molecules into the parenchyma and the concomitant fluctuations in the microenvironment following a transient breakdown of the blood-brain barrier (BBB) during ischemic/hypoxic conditions or because of an autoimmune disease are detrimental to the physiological functioning of nervous tissue. On the other hand, the treatment of neurological disorders is often hampered as only minimal amounts of therapeutic agents are able to penetrate a fully functional BBB or blood cerebrospinal fluid barrier. An in-depth understanding of the molecular machinery governing the establishment and maintenance of these barriers is necessary to develop rational strategies allowing a controlled delivery of appropriate drugs to the CNS. At the basis of such tissue barriers are intimate cell-cell contacts (zonulae occludentes, tight junctions) which are present in all polarized epithelia and endothelia. By creating a paracellular diffusion constraint TJs enable the vectorial transport across cell monolayers. More recent findings indicate that functional barriers are already established during development, protecting the fetal brain. As an understanding of the biogenesis of TJs might reveal the underlying mechanisms of barrier formation during ontogenic development numerous in vitro systems have been developed to study the assembly and disassembly of TJs. In addition, monitoring the stage-specific expression of TJ-associated proteins during development has brought much insight into the "developmental tightening" of tissue barriers. Over the last two decades a detailed molecular map of transmembrane and cytoplasmic TJ-proteins has been identified. These proteins not only form a cell-cell adhesion structure, but integrate various signaling pathways, thereby directly or indirectly impacting upon processes such as cell-cell adhesion, cytoskeletal rearrangement, and transcriptional control. This review will provide a brief overview on the establishment of the BBB during embryonic development in mammals and a detailed description of the ultrastructure, biogenesis, and molecular composition of epithelial and endothelial TJs will be given.
    Frontiers in Neuroscience 12/2014; 8:392. DOI:10.3389/fnins.2014.00392
  • [Show abstract] [Hide abstract]
    ABSTRACT: The NET subfamily of zinc finger proteins is an important mediator during developmental processes. The evolutionary conserved zinc finger protein ZNF503/ Zeppo2 (zinc finger elbow-related proline domain protein-2; Zpo2) plays critical roles during embryogenesis. We have found that Zpo2 is expressed in adult tissue and have examined its function. We find that Zpo2 is a nuclear-targeted transcriptional repressor that is expressed in mammary epithelial cells. Elevated Zpo2 levels increase mammary epithelial cell proliferation. Zpo2 promotes cellular invasion through downregulation of E-cadherin and regulates the invasive phenotype in a Rac1-dependent manner. We detect elevated Zpo2 expression during breast cancer progression in MMTV-PyMT transgenic mouse model. Tumor transplant experiments indicated that overexpression of Zpo2 in MMTV-PyMT mammary tumor cell lines enhances lung metastasis. Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; 290(6). DOI:10.1074/jbc.M114.611202 · 4.60 Impact Factor