title: Arg kinase regulates epithelial cell polarity by targeting β1-integrin and small GTPase pathways.
abstract: BACKGROUND
  Establishment and maintenance of epithelial cell polarity is regulated in part by signaling from adhesion receptors. Loss of cell polarity is associated with multiple pathologies including the initiation and progression of various cancers. The β1-integrin adhesion receptor plays a role in the regulation of cell polarity; however, the identity of the signaling pathways that modulate β1-integrin function and connect it to the regulation of polarity pathways remains largely unknown.
  
  
  RESULTS
  The present work identifies a role for Arg, a member of the Abl family nonreceptor tyrosine kinases, in the regulation of adhesive signals and epithelial cell polarity. In a three-dimensional cell culture model, activation of Arg kinase leads to a striking inversion of apical-basal polarity. In contrast, loss of Arg function impairs the establishment of a polarized epithelial cyst structure. Activated Arg kinase disrupts β1-integrin signaling and localization and impairs Rac1-mediated laminin assembly. Disruption of β1-integrin function by active Arg results in altered distribution of selected polarity complex components mediated in part by Rap1 GTPase signaling. Whereas polarity inversion is partially rescued by a constitutively active Rap1, Rac1-dependent laminin assembly is not, indicating that Rap1 and Rac1 signal independently during epithelial polarity.
  
  
  CONCLUSIONS
  These findings suggest that modulation of Arg kinase function may contribute not only to normal epithelial polarity regulation but also may promote pathologies associated with loss of cell polarity.
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Ran
authors: R
authors: Li
authors: Ann Marie
authors: AM
authors: Pendergast
mesh_terms: D000818:Animals; D016764:Cell Polarity; D002478:Cells, Cultured; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D019012:Integrin beta1; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D020558:GTP Phosphohydrolases; D020827:rap1 GTP-Binding Proteins