Integrin activation is needed to link the extracellular matrix with the actin cytoskeleton during cell motility. Protrusion requires coordination of actin dynamics with focal-adhesion turnover. We report that the adaptor protein liprin-α1 is stably associated with the cell membrane. Lipin-α1 shows a localization that is distinct from that of activated β1 integrins at the edge of spreading cells. Depletion of liprin-α1 inhibits the spreading of COS7 cells on fibronectin by affecting lamellipodia formation, whereas its overexpression enhances spreading, and lamellipodia and focal-adhesion formation at the cell edge. Cooperation between liprin-α1 and talin is needed, because either talin or liprin depletion prevents spreading in the presence of the other protein. The effects of liprin on spreading, but not its effects in the reorganization of the cell edge, are dependent on its interaction with leukocyte common antigen-related tyrosine phosphatase receptors. Therefore, liprin is an essential regulator of cell motility that contributes to the effectiveness of cell-edge protrusion.