A) Nascent FAs are formed at cell periphery by integrin and extracellular matrix (ECM) interactions. Inside cells, talin binding to integrin cytoplasmic tails establishes a linkage with the actin cytoskeleton and vinculin. Paxillin is also recruited to nascent FAs and FAK targeting to these sites is via interactions with talin and paxillin. FAK is regulated in part through an inhibitory intra-molecular interaction between the FAK FERM and the FAK kinase domains. In this inactive conformation, FAK FERM can bind the actin nucleating protein Arp3 and facilitate the recruitment of the Arp2/3 complex to nascent FAs. This linkage connects FAK to leading edge protrusions.
B) Integrin clustering, actin cytoskeletal tension, or binding of proteins or phospholipids to the FAK FERM domain can lead to the release of auto-inhibitory constraints and FAK catalytic activation resulting in FAK auto-phosphorylation at tyrosine (Y) 397. FAK activation leads to the formation of a complex with Src-family kinases and the increased phosphorylation of FAK and other substrate proteins within FAs such as p190RhoGAP. FAK-mediated phosphorylation of p190RhoGAP is important in the establishment of cell polarity and in the regulation of RhoA GTPase activity. As Arp2/3 does not interact strongly with activated FAK, its release upon FAK activation allows for Arp2/3 recruitment to the extended lamellipodia and branched actin filament assembly.

FAK can facilitate actin polymerization at nascent FAs by interacting with Arp2/3 complex and modulating Rho/Rac activation cycles, resulting in the stabilization of leading edge formation. FAK also promotes FA turnover at initial stages of cell spreading by RhoA inhibition, resulting in reduced cell contractility at nascent FAs. The organization of a stable leading edge facilitates cell polarity, resulting in Golgi orientation in the direction of cell migration. At later stages of cell migration, FAK promotes FA maturation via RhoA activation and increased cell contractility. At trailing edge FAs, FAK-mediated increased cell contractility via RhoA activation is associated with FA disassembly or turnover. Therefore, FAK acts to regulate multiple and differential steps required for efficient directional cell movement.

At early stages of cell spreading (15 to 45 min.), FAK forms a complex with p120RasGAP and p190RhoGAP resulting in localization of p190RhoGAP at nascent FAs. FAK-mediated phosphorylation of p190RhoGAP is associated with the inhibition of RhoA at leading edge FAs. As Rho and Rac activity can be antagonistic, Rho inhibition can also indirectly facilitate Rac activation. Low Rho and high Rac activity at the leading edge results in increased cell spreading, fuelled by f-actin polymerizaton and decreased cell contractility (PUSH). At later stages of cell spreading (60+ min.), FAK can balance the PUSH signal by recruiting and phosphorylating Rgnef (p190RhoGEF) at FA sites. Rgnef facilitates increased RhoA activation to promote cell contractility (PULL), resulting in increased tension at FA sites and promoting leading edge stability.