αvβ5/β6 integrin suppression leads to a stimulation of α2β1 dependent cell migration resistant to PI3K/Akt inhibition

Crosstalk between integrins is involved in the regulation of various cell functions including cell migration. Here we identify the interplay between the integrins αvβ5/β6 and α2β1 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 αvβ5/β6 function on α2β1, we decreased the expression of αv 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 α2β1 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 αvβ5/β6-dependent limitation of α2β1 function could be overridden by TS2/16, an activating anti-β1 antibody. Interestingly, compared to control cells, the pharmacological inhibition of PI3Kinase or the siRNA-mediated knockdown of AKT had little effect on the high α2β1-mediated cell migration observed in the absence of αv integrins or following activation of α2β1 integrins by the TS2/16. These results suggest that integrins αvβ5/β6 repress α2β1 possibly by interfering with their activation process and thereby modify the cell signaling regulation of α2β1-mediated migration.