title: PKCepsilon regulation of an alpha5 integrin-ZO-1 complex controls lamellae formation in migrating cancer cells.
abstract: Disruption of intercellular adhesions, increased abundance of alpha(5)beta(1) integrin, and activation of protein kinase Cepsilon (PKCepsilon) correlate with invasion and unfavorable prognosis in lung cancer. However, it remains elusive how these distinct factors contribute to the invasive behavior of cancer cells. Persistent cell motility requires the formation of stable lamellae at the leading edge of a migrating cell. Here, we report that the tight junction protein zonula occludens-1 (ZO-1) preferentially interacts with alpha(5)beta(1) integrin at the lamellae of migrating cells. Disruption of ZO-1 binding to an internal PDZ-binding motif in the alpha(5) cytoplasmic tail prevented the polarized localization of ZO-1 and alpha(5) at the leading edge. Furthermore, silencing of alpha(5) integrin inhibited migration and invasion of lung cancer cells, and silencing of ZO-1 resulted in increased Rac activity and reduced directional cell motility. The formation of the alpha(5)-ZO-1 complex was dependent on PKCepsilon: Phosphorylation of ZO-1 at serine-168 regulated the subcellular localization of ZO-1 and thus controlled its association with alpha(5) integrin. In conclusion, PKCepsilon activation drives the formation of a spatially restricted, promigratory alpha(5)-ZO-1 complex at the leading edge of lung cancer cells.
authors: Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, FIN-20520 Turku, Finland.
authors: Saara
authors: S
authors: Tuomi
authors: Anja
authors: A
authors: Mai
authors: Jonna
authors: J
authors: Nevo
authors: Jukka O
authors: JO
authors: Laine
authors: Vesa
authors: V
authors: Vilkki
authors: Tiina J
authors: TJ
authors: Ohman
authors: Carl G
authors: CG
authors: Gahmberg
authors: Peter J
authors: PJ
authors: Parker
authors: Johanna
authors: J
authors: Ivaska
mesh_terms: D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
chemical_list: D039564:Integrin alphaV; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D051744:Protein Kinase C-epsilon