PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells

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

PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells

  1. Saara Tuomi1,
  2. Anja Mai1,
  3. Jonna Nevo1,
  4. Jukka O. Laine2,
  5. Vesa Vilkki3,
  6. Tiina J. Öhman4,
  7. Carl G. Gahmberg4,
  8. Peter J. Parker5,6, and
  9. Johanna Ivaska1,7,*
  1. 1Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, FIN-20520 Turku, Finland.
  2. 2Department of Pathology, University of Turku, FIN-20520 Turku, Finland.
  3. 3Department of Surgery, University Hospital Turku, FIN-20520 Turku, Finland.
  4. 4Division of Biochemistry, Faculty of Biosciences, University of Helsinki, FIN-00014 Helsinki, Finland.
  5. 5Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK.
  6. 6King’s College London, Division of Cancer Studies, Guy’s Hospital, London SE1 1UL, UK.
  7. 7Department of Biochemistry and Food Chemistry, University of Turku, FIN-20520 Turku, Finland.
  1. *To whom correspondence should be addressed. E-mail: Johanna.ivaska{at}vtt.fi

Abstract

Disruption of intercellular adhesions, increased abundance of α5β1 integrin, and activation of protein kinase Cɛ (PKCɛ) 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 α5β1 integrin at the lamellae of migrating cells. Disruption of ZO-1 binding to an internal PDZ-binding motif in the α5 cytoplasmic tail prevented the polarized localization of ZO-1 and α5 at the leading edge. Furthermore, silencing of α5 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 α5–ZO-1 complex was dependent on PKCɛ: Phosphorylation of ZO-1 at serine-168 regulated the subcellular localization of ZO-1 and thus controlled its association with α5 integrin. In conclusion, PKCɛ activation drives the formation of a spatially restricted, promigratory α5–ZO-1 complex at the leading edge of lung cancer cells.

Citation:

S. Tuomi, A. Mai, J. Nevo, J. O. Laine, V. Vilkki, T. J. Öhman, C. G. Gahmberg, P. J. Parker, and J. Ivaska, PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. Sci. Signal. 2, ra32 (2009).

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