Epidermal growth factor receptor–Epidermal growth factor receptor pathway substrate 8 (EGFR–EPS8) protein–protein interface (EGFR–EPS8 interface)

The Epidermal growth factor receptor–Epidermal growth factor receptor pathway substrate 8 (EGFR–EPS8) protein–protein interface is a critical regulatory node in the EGFR signaling pathway. EPS8 is a multi-functional adapter protein that binds to EGFR, facilitating downstream signaling cascades such as the Ras-MAPK and PI3K-Akt pathways (UniProt Q12929). This interaction is essential for coordinating actin cytoskeleton remodeling and regulating the endocytic trafficking of the receptor, which determines the duration and intensity of cellular signaling (PMID: 15103331). In many cancers, including glioblastoma and pancreatic cancer, EPS8 is overexpressed and stabilizes EGFR, promoting tumor cell proliferation, invasion, and resistance to conventional tyrosine kinase inhibitors (PMID: 24631444). The interface specifically involves the SH3 domain of EPS8 and the juxtamembrane or C-terminal regions of EGFR (PMID: 10406323). Targeting this specific interface with small molecules or peptidomimetics offers a strategy to disrupt oncogenic signaling while potentially overcoming resistance mechanisms associated with the EGFR kinase domain. As a protein-protein interaction target, it provides a more specific point of intervention compared to broad-spectrum kinase inhibition. Current research focuses on developing inhibitors that block the EPS8-SH3 domain to prevent its association with the receptor complex.

Other names

EGFR-EPS8 complexEPS8-EGFR interactionEpidermal growth factor receptor-EPS8 interface

Inhibition of the physical interaction between the EGFR receptor and the EPS8 adapter protein to disrupt oncogenic signaling and receptor trafficking.