Focal Adhesion Kinase Induces Matrix Metalloproteinase-2 by Involving α5β1-Mediated Signaling in Breast Cancer Cell, MCF-7.

ABSTRACT

Introduction: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a pivotal role in cell invasion. Matrix metalloproteinases (MMPs) are implicated as the key players in cancer cell invasion. Hence, the role of FAK in MMP regulation is very important in understanding tumor progression. Materials and Methods: Here, we studied the role of FAK, its association with other signaling kinases and involvement in the α5β1 integrin receptor-mediated regulation of MMP-2 activity and expression in human breast cancer cell line MCF-7. Results: Immuno blot analysis revealed that FN treatment causes phosphorylation of FAK and FAK gets localized at the cell attachment focal point of MCF-7 cells. FN treatment did not change the mRNA status of FAK but enhanced mRNA level of MMP-2 and MT1-MMP, also caused downregulation of TIMP-2. Co-imunoprecipitation and inhibitor studies revealed the association of FAK with α5β1, Paxillin, PI3K and ERK. siRNA studies revealed that FAK is critical in regulation of activity and expression of MMP-2 and downstream signaling kinases. Conclusion: Th e interaction of α5β1 integrin with FN initiates a signaling cascade with FAK as its central player. FAK gets phosphorylated and in turn associates with tyrosine kinases like PI3K and ERK. FAK also activates PI3K and ERK that serve as very crucial mediators of the signaling pathway leading to induction of MMP-2 activity and resulting invasion of breast cancer cell, MCF-7.