Abstract A77: Transmembrane 4 L six family member 5 (TM4SF5) regulates FAK/c-Src signaling activity for cell migration and invasion

Abstract

Abstract Transmembrane 4 L six family member 5 (TM4SF5) is a transmembrane glycoprotein of the transmembrane 4 L six family and highly expressed in many types of cancers. In addition to diverse tumorigenic functions, TM4SF5 also plays roles in migration and invasion, leading to lung metastasis of TM4SF-positive cells injected into tail veins. To understand the TM4SF5-mediated metastatic roles, we mechanistically explored TM4SF5-mediated signaling pathways for migration and invasion. Using endogenously or exogenously TM4SF5-null or -expressing hepatocytes in vitro and mouse animals in vivo, we revealed how TM4SF5 mediated the metastatic processes along the leading edges of migratory/invasive cells. The intracellular loop of TM4SF5 directly and adhesion-dependently bound FAK with causing a structural alteration possibly to release the inhibitory intramolecular interaction, which activated FAK at the leading edges of cells to promote migration/invasion and in vivo metastasis. Impaired interactions between TM4SF5 and FAK attenuated phospho-FAK, signaling link to actin organization machinery, and metastatic potentials. Meanwhile, the cytosolic C-terminus of TM4SF5 bound c-Src that led to invasive protrusion formation. Wildtype TM4SF5 expression enhanced invasive protrusion formation in a c-Src-dependent manner, compared with TM4SF5-null control hepatocytes, but tailless TM4SF5ΔC cells were more efficient than were wildtype TM4SF5 cells, suggesting a negatively regulatory role by its C-terminus. c-Src activity of TM4SF5 WT- or TM4SF5ΔC-expressing cells EGF-independently correlated with enhanced phospho-Tyr845 in EGFR for the invasive protrusions. Altogether, this study suggests that TM4SF5 is involved in signaling for migration and invasion and is a promising target for the treatment of TM4SF5-positively metastatic cancer. Citation Format: Oisun Jung, Yoon-Ju Choi, Jung Weon Lee. Transmembrane 4 L six family member 5 (TM4SF5) regulates FAK/c-Src signaling activity for cell migration and invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A77.