Kinase Family FAK
Kinase Classification: Group TK: Family FAK
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Evolution
FAK is found in all animals studied and in most choanoflagellates, correlating with its role in intercellular complexes. Two homologs are found in vertebrates, FAK (PTK2) and PYK2 (FAK2).
Domain Structure
FAKs have an N-terminal FERM/B41 domain followed by a tyrosine kinase domain and a Focal_AT (or FAT) domain. Sponges have a divergent FERM domain which is not usually annotated,, while choanoflagellates have little or no similarity in the Focal_AT region.
Functions
FAK is associated with Focal Adhesions, areas where transmembrane integrins link the extracellular matrix to the cytoskeleton, and functions to regulate the interaction of extracellular and intracellular signals, as wel as cell migration and shape changes. As a long (>1000 AA), multi-domain protein, it acts both as a scaffold and as an active protein kinase. The FERM domain binds the cytoskeletal protein ezrin, and mediates interactions with several receptor tyrosine kinases, while the FAT domain recruits the protein to focal adhesions by binding to talin and paxillin, and links to several Rho GEFs, which regulate the cytoskeleton
FAK is activated by autophosphorylation at the active site as well as by upstream kinases including Src, and by exctracellular matrix. Loss of FAK causes increased focal contacts, and FAK signaling is implicated in disassembly of these focal contacts.
Proline-rich regions between the annotated domains serve as SH3 domain docking sites, and in particular, bind p130Cas, which binds and activates the Src tyrosine kinase. p130Cas and paxillin are both confirmed phosphorylation targets of FAK. Cas phosphorylation is associated with activation of the small GTPase Rac, while paxillin phosphoryaltion is associated with focal adhesion turnover.
References
- Mitra SK, Hanson DA, and Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68. DOI:10.1038/nrm1549 |
- Tan X, Yan Y, Song B, Zhu S, Mei Q, and Wu K. Focal adhesion kinase: from biological functions to therapeutic strategies. Exp Hematol Oncol. 2023 Sep 25;12(1):83. DOI:10.1186/s40164-023-00446-7 |
