Integrin-specific activation of Rac controls progression through the G1 phase of the cell cycle

Adhesion to fibronectin through the alpha5 beta1 integrin enables endothelial cells to proliferate in response to growth factors, whereas adhesion to laminin through alpha2 beta1 results in growth arrest under the same conditions. On laminin, endothelial cells fail to translate Cyclin D1 mRNA and activate CDK4 and CDK6. Activated Pac, but not MEK1, PI-3K, or Akt, rescues biosynthesis of cyclin D1 and progression through the G(1) phase. Conversely, dominant negative Pac prevents these events on fibronectin. Mitogens promote activation of Pac on fibronectin but not laminin. This process is mediated by SOS and PI-3K and requires coordinate upstream signals through Shc and FAK. These results indicate that Pac is a crucial mediator of the integrin-specific control of cell cycle in endothelial cells.