Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation.
Highlights
Focal adhesion kinase (FAK) was discovered almost three decades ago as a kinase that is highly phosphorylated in response to cell adhesion and localisation into the focal adhesion complex [1,2]
High resolution structures of FAK regions, including all portions predicted to adopt globular domains, have provided important insights into the architecture and function of FAK at atomic level. These structures have defined the mechanism of FAK autoinhibition in the cytosol [35] and identified a number of interactions, including a mode of recruitment into focal adhesions via paxillin [53,54] and FERM mediated dimerization important for activation [44]
Important future challenges include a structural understanding of how FAK integrates in its various cellular environments and how this leads to structural rearrangements that affect FAK activity, its interaction network or localisation
Summary
Focal adhesion kinase (FAK) was discovered almost three decades ago as a kinase that is highly phosphorylated in response to cell adhesion and localisation into the focal adhesion complex [1,2]. FAK is today recognised as a hub in the interactome of focal adhesions [19,20,21], a protein complex at the centre of mesenchymal cell migration. In addition to the structural role of focal adhesions in transmitting force for cell motility, the application of force to the complex triggers important signalling cascades in the membrane proximal signalling layer. FAK is a key component of the focal adhesion signalling layer and is shown to directly interact with membrane lipids [25,26]. Force generation in focal adhesions is shown to activate FAK [27,28,29] and its signals regulate the controlled maturation and turnover of the focal adhesion complex, cell spreading and migration, and via extensive cross-talk feed into proliferative and survival signals [11].
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