Focal Adhesion Kinase Signaling in Cell Motility and Migration

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates the dynamic interplay between cells and their extracellular matrix. Localised to multiprotein complexes termed focal adhesions, FAK is recruited upon integrin engagement and activated through autophosphorylation at Tyr-397. This primary event nucleates the binding of Src family kinases and adaptor proteins such as paxillin and talin, establishing signalling hubs that regulate actin remodelling, adhesion turnover and directional force transmission. Mechanical inputs—both from substrate stiffness and cytoskeletal contractility—further modulate FAK conformation and activity, enabling it to function as a mechanosensor. Downstream effectors include Rho GTPases, MAP kinases and PI3K–Akt pathways, which collectively coordinate lamellipodial extension, cell polarity and migration speed. FAK signalling is indispensable for processes as diverse as embryonic morphogenesis, vascular remodelling and epithelial wound closure. In pathological contexts, aberrant FAK activation underpins tumour invasion and metastasis, while its modulation holds promise for regenerative medicine and anti-fibrotic strategies.

Research from Nature Portfolio

Recent studies have elucidated how force-dependent coupling of traction and FAK phosphorylation at individual adhesions underpins tissue-scale repair. By measuring local traction forces on defined substrates, it was shown that FAK Tyr-397 phosphorylation and protein recruitment increase linearly with applied force on rigid matrices, a process requiring talin–FAK binding and vinculin engagement. A kinetic model of talin–FAK interactions under tension recapitulates these observations and reveals how mechanosignalling drives collective cell migration in three-dimensional wound assays. In parallel, small-molecule activation of FAK has demonstrated the therapeutic potential of direct Tyr-397 agonism. A drug-like compound was found to selectively enhance FAK phosphorylation without off-target kinase activation, accelerating epithelial monolayer closure in vitro and promoting mucosal ulcer healing in murine models. Notably, this restitution occurred independently of cell proliferation, highlighting a strategy to stimulate migration-driven repair while avoiding hyperplasia.

Focal Adhesion Kinase Signaling in Cell Motility and Migration publication trend

The graph below shows the total number of articles in focal adhesion kinase signaling in cell motility and migration across all publications each year (not limited to Nature Index journals).

Technical terms

Focal adhesion kinase (FAK): A cytoplasmic tyrosine kinase that links integrin engagement to intracellular signalling and mechanotransduction.

Integrin: A transmembrane receptor that binds extracellular matrix proteins and recruits focal adhesion components.

Paxillin: A cytoskeletal adaptor protein that binds FAK and regulates assembly and disassembly of focal adhesions.

Talin: A protein that connects integrins to the actin cytoskeleton and transmits mechanical force to FAK.

FRNK: FAK-related non-kinase, a truncated paralogue that competes with FAK at adhesions to stabilise cell–matrix contacts.

Mechanotransduction: The process by which cells convert mechanical stimuli into biochemical signals, often via force-sensitive proteins.

References

1. Identification of a novel type of focal adhesion remodelling via FAK/FRNK replacement, and its contribution to cancer progression. Cell Death & Disease (2023).
2. FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions. Biomolecules (2020).
3. Force-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair. Nature Communications (2021).
4. Small molecule FAK activator promotes human intestinal epithelial monolayer wound closure and mouse ulcer healing. Scientific Reports (2019).
5. Inhibiting FAK–Paxillin Interaction Reduces Migration and Invadopodia-Mediated Matrix Degradation in Metastatic Melanoma Cells. Cancers (2021).