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Raf kinase inhibitor protein positively regulates cell-substratum adhesion while negatively regulating cell-cell adhesion

Mc Henry, Kevin T.
Zhu, Shoutian
Beshir, Anwar B.
Tang, Hui-Hui
Yeung, Kam C.
Fenteany, Gabriel
Published in Journal of Cellular Biochemistry. 2008, vol. 103, no. 3, p. 972-85
Abstract Raf kinase inhibitor protein (RKIP) regulates a number of cellular processes, including cell migration. Exploring the role of RKIP in cell adhesion, we found that overexpression of RKIP in Madin-Darby canine kidney (MDCK) epithelial cells increases adhesion to the substratum, while decreasing adhesion of the cells to one another. The level of the adherens junction protein E-cadherin declines profoundly, and there is loss of normal localization of the tight junction protein ZO-1, while expression of the cell-substratum adhesion protein beta1 integrin dramatically increases. The cells also display increased adhesion and spreading on multiple substrata, including collagen, gelatin, fibronectin and laminin. In three-dimensional culture, RKIP overexpression leads to marked cell elongation and extension of long membrane protrusions into the surrounding matrix, and the cells do not form hollow cysts. RKIP-overexpressing cells generate considerably more contractile traction force than do control cells. In contrast, RNA interference-based silencing of RKIP expression results in decreased cell-substratum adhesion in both MDCK and MCF7 human breast adenocarcinoma cells. Treatment of MDCK and MCF7 cells with locostatin, a direct inhibitor of RKIP and cell migration, also reduces cell-substratum adhesion. Silencing of RKIP expression in MCF7 cells leads to a reduction in the rate of wound closure in a scratch-wound assay, although not as pronounced as that previously reported for RKIP-knockdown MDCK cells. These results suggest that RKIP has important roles in the regulation of cell adhesion, positively controlling cell-substratum adhesion while negatively controlling cell-cell adhesion, and underscore the complex functions of RKIP in cell physiology.
Keywords Adherens Junctions/metabolismAnimalsAntigens, CD29/metabolismBreast Neoplasms/metabolism/pathologyCadherins/metabolismCell Movement/drug effectsCell-Matrix Junctions/drug effects/metabolismDogsDown-RegulationEpithelial Cells/metabolismExtracellular Matrix/metabolismExtracellular Matrix Proteins/chemistry/metabolismHumansKidney Neoplasms/metabolism/pathologyMembrane Proteins/metabolismOxazolidinones/pharmacologyPhosphatidylethanolamine Binding Protein/metabolism/pharmacologyPhosphoproteins/metabolismProtein Kinase Inhibitors/metabolism/pharmacologyRNA InterferenceTumor Cells, CulturedUp-RegulationWound Healing/drug effectsRaf Kinases/antagonists & inhibitors
PMID: 17668446
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MC HENRY, Kevin T. et al. Raf kinase inhibitor protein positively regulates cell-substratum adhesion while negatively regulating cell-cell adhesion. In: Journal of cellular biochemistry, 2008, vol. 103, n° 3, p. 972-85. doi: 10.1002/jcb.21470 https://archive-ouverte.unige.ch/unige:2110

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Deposited on : 2009-06-19

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