alpha v beta 5/beta 6 integrin suppression leads to a stimulation of alpha 2 beta 1 dependent cell migration resistant to PI3K/Akt inhibition

Abstract : Crosstalk between integrins is involved in the regulation of various cell functions including cell migration. Here we identify the interplay between the integrins alpha v beta 5/beta 6 and alpha 2 beta 1 during cell migration toward type I collagen. Human colon cancer cell lines HT29-D4 and SW480 were used as cell models. To improve our Understanding of the consequences of alpha v beta 5/beta 6 function on alpha 2 beta 1, we decreased the expression of alpha v integrins by either siRNA or lysosomal targeting strategies, or inhibited their function using, as antagonists, blocking antibodies or disintegrins. In all cases, we observed a greatly enhanced alpha 2 beta 1 integrin-dependent cell migration associated with focal adhesion rearrangements and increased outside-in signaling as demonstrated by elevated phosphorylation of focal adhesion kinase and MAPKinase (ERK1 and ERK2). The alpha v beta 5/beta 6-dependent limitation of alpha 2 beta 1 function could be overridden by TS2/16, an activating anti-beta 1 antibody. Interestingly, compared to control cells, the pharmacological inhibition of PI3Kinase or the siRNA-mediated knockdown of AKT had little effect on the high alpha 2 beta 1-mediated cell migration observed in the absence of alpha v integrins or following activation of alpha 2 beta 1 integrins by the TS2/16. These results suggest that integrins alpha v beta 5/beta 6 repress alpha 2 beta 1 possibly by interfering with their activation process and thereby modify the cell signaling regulation of alpha 2 beta 1-mediated migration. (C) 2009 Elsevier Inc. All rights reserved.
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Céline Defilles, Jean-Claude Lissitzky, Marie-Pierre Montero, Frédéric André, Charles Prevot, et al.. alpha v beta 5/beta 6 integrin suppression leads to a stimulation of alpha 2 beta 1 dependent cell migration resistant to PI3K/Akt inhibition. Experimental Cell Research, Elsevier, 2009, 315 (11), pp.1840-1849. ⟨10.1016/j.yexcr.2009.03.014⟩. ⟨pasteur-01375182⟩

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