Focal adhesion kinase focal adhesion targeting domain (FAK FAT domain) (FAK FAT domain)

The Focal Adhesion Kinase (FAK) Focal Adhesion Targeting (FAT) domain is a C-terminal structural module of the non-receptor tyrosine kinase FAK (PTK2) (UniProt Q05397). It consists of a four-helix bundle that contains two distinct hydrophobic patches, one of which serves as the binding interface for the LD2 motif of the scaffold protein paxillin (PMID: 11051551). This specific protein-protein interaction is essential for the recruitment of FAK to focal adhesions, where it integrates signals from integrins and growth factor receptors to regulate cell motility, survival, and proliferation (PMID: 12192574). In various malignancies, the FAK-paxillin interaction is frequently exploited to promote tumor invasion and metastasis, making this interface a high-value target for anti-cancer therapy (PMC3857604). While most clinical FAK inhibitors, such as Defactinib, target the kinase domain's catalytic activity, the FAT domain LD2-binding interface offers a distinct site for small-molecule intervention to disrupt FAK's scaffolding functions (PMID: 24333720). Experimental inhibitors like the compound C4 have demonstrated the feasibility of targeting this interface to reduce tumor growth and spread by specifically blocking FAK localization (PMID: 17452457).

Other names

PTK2 FAT domainFocal adhesion targeting domainFAK C-terminal domainProtein-tyrosine kinase 2 FAT domain

Disruption of the protein-protein interaction between the FAK FAT domain and the paxillin LD2 motif, preventing FAK recruitment to focal adhesions and inhibiting downstream signaling pathways involved in cell migration and survival (PMID: 12192574, PMID: 24333720).