FIGURE 1 | Biogenesis of focal adhesions.

a | Many integrins that are not bound to the extracellular matrix (ECM) are present on the cell surface in an inactive conformation, which is characterized by 'bent' extracellular domains that mask the ECM-binding pocket. This conformation is stabilized by interactions between integrin transmembrane domains, membrane-proximal extracellular domains and a salt bridge between the cytoplasmic domains. b | When talin is recruited to the plasma membrane and activated in association with phosphatidylinositol phosphate kinase type-I (PIPKI), it binds to the cytoplasmic tail of integrins¹²⁰. This interaction separates the cytoplasmic domains and induces the integrins to adopt the 'primed' conformation. c | The integrin extracellular domains extend and unmask the ligand-binding site, allowing the integrin to bind specific ECM molecules. The separated integrin cytoplasmic domains and talin form a platform for the recruitment of other focal-adhesion proteins. Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin. Other proteins such as vinculin and focal adhesion kinase (FAK) are recruited to the nascent focal complex in a sequential manner¹²¹. The maturation of focal adhesions involves clustering of active, ligand-bound integrins and the assembly of a multiprotein complex that is capable of linking integrins to the actin cytoskeleton and communicating with signalling pathways.

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