Focal adhesion kinase (FAK)–Vascular endothelial growth factor receptor 3 (VEGFR-3) protein–protein interface (FAK–VEGFR-3 PPI)

The Focal adhesion kinase (FAK)–Vascular endothelial growth factor receptor 3 (VEGFR-3) protein–protein interface is a critical regulatory node in lymphangiogenesis and tumor metastasis (Kurenova et al., 2009, JBC). FAK, a non-receptor tyrosine kinase, physically associates with the cytoplasmic domain of VEGFR-3, a receptor tyrosine kinase primarily expressed in lymphatic endothelial cells (UniProt P48594, Q05397). This interaction facilitates the phosphorylation of FAK and activates downstream signaling cascades, including the PI3K/AKT and MAPK/ERK pathways, which promote the proliferation, migration, and survival of lymphatic cells. In the context of oncology, the FAK–VEGFR-3 complex is often upregulated, driving the formation of new lymphatic vessels that serve as conduits for cancer cell dissemination to regional lymph nodes (Soni et al., 2020, Cancer Res). Targeting this specific protein-protein interface, rather than the catalytic activity of the individual kinases, offers a strategy to selectively inhibit pathological lymphangiogenesis while potentially reducing the systemic toxicity associated with broad-spectrum kinase inhibitors. Experimental small molecules, such as the compound C4, have demonstrated the ability to disrupt this interface, leading to decreased tumor-induced lymphangiogenesis and reduced metastatic spread in preclinical models.

Other names

FAK-VEGFR3 interactionPTK2-FLT4 protein-protein interfaceFAK-VEGFR3 complexFAK-VEGFR3 signaling axis

Disruption of the physical interaction between the FAK FERM domain and the VEGFR-3 cytoplasmic domain, thereby inhibiting downstream signaling pathways such as AKT and ERK that drive lymphangiogenesis.