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

Saara Tuomi, Anja Mai, Jonna Nevo, Jukka O. Laine, Vesa Vilkki, Tiina J. Öhman, Carl G. Gahmberg, Peter J. Parker, Johanna Ivaska (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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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.
Original languageEnglish
Article numberra32
JournalScience Signaling
Volume2
Issue number77
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

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Tight Junctions
Integrins
Protein Kinase C
Cells
Lung Neoplasms
Neoplasms
Chemical activation
Tight Junction Proteins
Phosphorylation
Cell Movement
Serine
Adhesion
Association reactions

Cite this

Tuomi, S., Mai, A., Nevo, J., Laine, J. O., Vilkki, V., Öhman, T. J., ... Ivaska, J. (2009). PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. Science Signaling, 2(77), [ra32]. https://doi.org/10.1126/scisignal.2000135
Tuomi, Saara ; Mai, Anja ; Nevo, Jonna ; Laine, Jukka O. ; Vilkki, Vesa ; Öhman, Tiina J. ; Gahmberg, Carl G. ; Parker, Peter J. ; Ivaska, Johanna. / PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. In: Science Signaling. 2009 ; Vol. 2, No. 77.
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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.",
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Tuomi, S, Mai, A, Nevo, J, Laine, JO, Vilkki, V, Öhman, TJ, Gahmberg, CG, Parker, PJ & Ivaska, J 2009, 'PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells', Science Signaling, vol. 2, no. 77, ra32. https://doi.org/10.1126/scisignal.2000135

PKCɛ Regulation of an α5 Integrin–ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells. / Tuomi, Saara; Mai, Anja; Nevo, Jonna; Laine, Jukka O.; Vilkki, Vesa; Öhman, Tiina J.; Gahmberg, Carl G.; Parker, Peter J.; Ivaska, Johanna (Corresponding Author).

In: Science Signaling, Vol. 2, No. 77, ra32, 2009.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

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AU - Tuomi, Saara

AU - Mai, Anja

AU - Nevo, Jonna

AU - Laine, Jukka O.

AU - Vilkki, Vesa

AU - Öhman, Tiina J.

AU - Gahmberg, Carl G.

AU - Parker, Peter J.

AU - Ivaska, Johanna

PY - 2009

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N2 - 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.

AB - 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.

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VL - 2

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

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ER -