The COOH-terminus of TM4SF5 in hepatoma cell lines regulates c-Src to form invasive protrusions via EGFR Tyr845 phosphorylation

► The C-terminus of TM4SF5 binds c-Src family kinases in preference to the inactive form. ► TM4SF5 requires a signaling link from c-Src to Tyr845 EGFR for invasive protrusion. ► Tailless TM4SF5 enhances c-Src/EGFR-dependent invasion even without EGF treatment. ► The C-terminus of TM4SF5 may play a negative regulatory role in hepatocyte invasion.