Activation of FAK by integrin β4 in an EGFR/Src dependent manner in tumor progression
Date Issued
2009
Date
2009
Author(s)
Tai, Yu-Ling
Abstract
Focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, is an important downstream mediator of integrins which belong to one family of cell adhesion receptors consisted of α and β subunits. Both integrin β4 and FAK play important roles in the tumor progression according to numerous previous reports, one report had shown integrin β4 can stimulate FAK’s activity, furthermore, it can interfere the integrin β4-mediated metastasis of invasive tumor. Here, we demonstrated a physical and functional association between these two molecules in vivo and in vitro. In the immunofluorescence staining assay, integrin β4 and FAK were co-localized at cell peripheral plasma membrane in MDA-MB 231 cell line, but not in non-aggressive MCF-7 tumor cell line. We also investigate that integrin β4 and FAK were over expression in human colon cancer by immunohistochemistry and Western blotting assay. According to co-immunoprecipitation, pull down and far Western assays, we conclude that a 25 amino-acid motif within FAK’s N terminus is responsible for interacting with the cytoplasmic tail of integrin β4. Furthermore, three of the 25 amino acids within the amino-terminus of FAK act as crucial sites in interaction with integrin β4. The interaction resulted in phosphorylation and activation of FAK in an adhesion-dependent manner. Furthermore, the particular interaction between integrin β4 and FAK is promoted by Src which subsequently affects STAT3 and AKT as the downstream signaling mediators upon this interaction. In addition, in both of HCT116 and MDA-MB-231 cells, disruption of this interaction reduced cell proliferation, motility and invasion, suggesting the involvement of this interaction in tumorigenesis and perhaps metastasis in these tumor cells. Our data resolved for the first time a novel pathway of integrin β4-mediated cellular functions via direct interaction with FAK in the regulation of tumor progression, thereby strengthening a link between integrin β4 and FAK biochemically and functionally.
Subjects
integrin β4
metastasis
tumorigenesis
cancer therapy
SDGs
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