Abstract C44: Activation of focal adhesion kinase by direct interaction with β4 integrin in an EGFR-Src-dependent pathway in tumor progression

Abstract

Abstract Although β4 integrin and FAK (focal adhesion kinase) are individually known to be associated with tumor progression, only recently have they been suggested to function in a signaling axis. Here, we demonstrate in vivo and in vitro physical and functional interactions between β4 integrin and FAK. An 11-amino acid motif of FAK was identified as essential for interaction with the cytodomain of β4 integrin in malignant cells but not in less malignant cells, implicating the role of this interaction in malignancies. Furthermore, this interaction occurs in an adhesion-dependent manner and results in autophosphorylation of FAK's Tyr-397. EGF signaling and Src activity were indispensable for this interaction. Finally, disruption of the β4 integrin/FAK complexes reduced cell proliferation, migration and invasion as well as tumorigenesis, in concurrence with the decreases in phospho-Akt and phospho-p38. Together, our data elucidate an underlying mechanism for the regulation of tumor progression by the novel β4 integrin/FAK complexes through a physical interaction that is EGF/Src dependent. The significance of this finding is highlighted by often co-overexpression of both integrin β4 and FAK in patients' cancerous tissues with colon cancer revealed by immunohistochemistry analyses. Based on the structural prediction for the complex of integrin β4 and FAK, it may lead us to gain more insight on the anticancer therapies of aggressive cancers. Citation Format: Yu-Ling Tai, Tang-Long Shen. Activation of focal adhesion kinase by direct interaction with β4 integrin in an EGFR-Src-dependent pathway in tumor progression. [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 C44.