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Sci. Signal., 30 June 2009
Vol. 2, Issue 77, p. ra32
[DOI: 10.1126/scisignal.2000135]

RESEARCH ARTICLES

PKC{varepsilon} Regulation of an {alpha}5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells

Saara Tuomi1, Anja Mai1, Jonna Nevo1, Jukka O. Laine2, Vesa Vilkki3, Tiina J. Öhman4, Carl G. Gahmberg4, Peter J. Parker5,6, and Johanna Ivaska1,7*

1 Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, FIN-20520 Turku, Finland.
2 Department of Pathology, University of Turku, FIN-20520 Turku, Finland.
3 Department of Surgery, University Hospital Turku, FIN-20520 Turku, Finland.
4 Division of Biochemistry, Faculty of Biosciences, University of Helsinki, FIN-00014 Helsinki, Finland.
5 Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK.
6 King’s College London, Division of Cancer Studies, Guy’s Hospital, London SE1 1UL, UK.
7 Department of Biochemistry and Food Chemistry, University of Turku, FIN-20520 Turku, Finland.

Abstract: Disruption of intercellular adhesions, increased abundance of {alpha}5β1 integrin, and activation of protein kinase C{varepsilon} (PKC{varepsilon}) 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}5β1 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 PKC{varepsilon}: 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, PKC{varepsilon} activation drives the formation of a spatially restricted, promigratory {alpha}5–ZO-1 complex at the leading edge of lung cancer cells.

* To whom correspondence should be addressed. E-mail: Johanna.ivaska{at}vtt.fi

Citation: S. Tuomi, A. Mai, J. Nevo, J. O. Laine, V. Vilkki, T. J. Öhman, C. G. Gahmberg, P. J. Parker, J. Ivaska, PKC{varepsilon} Regulation of an {alpha}5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. Sci. Signal. 2, ra32 (2009).

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