FAK

FAK, short for focal adhesion kinase, is a non-receptor protein tyrosine kinase encoded by the PTK2 gene in humans. It localizes to focal adhesions, where it coordinates signals from integrins and growth factors to regulate cell adhesion, migration, proliferation, and survival.

FAK has a three-part domain structure: an N-terminal FERM domain that mediates interactions with integrins and receptor tyrosine kinases, a central kinase domain, and a C-terminal focal adhesion targeting (FAT) domain that anchors FAK to focal adhesions. Activation begins with integrin engagement and autophosphorylation at tyrosine 397 (Y397), creating a binding site for Src family kinases. Src then phosphorylates FAK at additional sites, including Y576 and Y577, fully activating the kinase and propagating downstream signaling through pathways such as PI3K-Akt and MAPK. The FAT domain supports localization and scaffolding through interactions with adaptor proteins like paxillin and talin, and FAK participates in mechanotransduction by linking extracellular matrix stiffness to downstream responses.

Functions of FAK extend to regulation of adhesion turnover, cell movement, proliferation, and survival, as well as roles in development, angiogenesis, wound healing, and immune signaling.

Clinical relevance centers on dysregulation of FAK in various cancers, where upregulation or hyperactivation can promote invasion and metastasis. Consequently, multiple small-molecule inhibitors targeting FAK have been developed and tested in preclinical and clinical settings, including defactinib (VS-6063) and GSK2256098. While preclinical models show reduced invasion and enhanced therapeutic responses, clinical results are ongoing and focus on efficacy, selectivity, and tissue-specific effects.

Genetically, PTK2 encodes FAK; complete knockout in mice causes early embryonic lethality, underscoring essential developmental roles, while the related kinase PYK2 (PTK2B) can partially compensate in some contexts.