Two distinct integrin binding sites on MMP9 drive cancer invasion by mediating integrin membrane trafficking & stabilization
Dutta, S.; Sarkar, S.; Tolani, S.; Hazari, M. A.; Sen, S.
Show abstract
Matrix stiffening has been established to drive cancer progression through increased activity of matrix metalloproteases (MMPs) which degrade the matrix creating paths for migration. However, the non-proteolytic functions of MMPs in cancer invasion remain relatively less understood. Here we have probed the importance of proteolytic and non-proteolytic functions of MMP9, which exhibits robust stiffness dependent expression and secretion in highly invasive cancer cells. We show that while MMP9 sustains spreading and 2D migration non-proteolytically by stabilizing focal adhesions, MMP9 proteolytic activity is essential for 3D invasion. We then establish the function of two distinct integrin {beta}1 (ITG {beta}1) binding sites on MMP9, with the hemopexin domain mediating co-packaging and co-transport of ITG {beta}1/MMP9 to the cell periphery, and the RGD domain stabilizing ITG {beta}1 on the cell membrane prior to matrix degradation. Together, our results illustrate how MMP9 optimizes cancer invasion by spatiotemporally integrating matrix remodeling with adhesion formation.
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