**5.2.3 Cell-substrate adhesions**

Newly formed focal adhesion complexes are localized in the lamellipodia of most migrating cells. Once the lamellipodium attach to the ECM, integrins come into contact with ECM ligands and cluster in the cell membrane where they interact with FAK, α-actin, and talin (Cox and Huttenlocher 1998). All these proteins can bind to adaptor proteins through Srchomologous domain 2 and 3 (SH2, SH3) as well as proline rich domains to more actin binding proteins (vinculin, paxillin and α-actin) and regulatory molecules PI3K to focal complexes (Zamir and Geiger 2001). Rac is required for focal complex assembly, and Rac itself can be activated by cell-substrate ECM adhesion (Rottner, Hall et al. 1999). It is suggested that the adhesion assemblies in migrating cells begin with small-scale clustering and the speed of the cell migration is dependent on ECM composition, which determines the relative activated levels of Rho, Rac and Cdc42 (Price, Leng et al. 1998). Therefore, interactions between ECM and integrins at the leading edge of cells play an important role in maintaining the level of active Rac. This indicates the existence of a positive feedback loop that allows continuous crosstalk between integrins and Rac, and allows cells to respond to changing ECM composition.
