alpha 5 beta 1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site

作者：Miroshnikova Y A; Rozenberg G I; Cassereau L; Pickup M; Mouw J K; Ou G; Templeman K L; Hannachi E I; Gooch K J; Sarang Sieminski A L; Garcia A J; Weaver V M^*

来源：Molecular Biology of the Cell, 2017, 28(22): 2958-2977.

DOI：10.1091/mbc.E17-02-0126

Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor alpha 5 beta 1 integrin. Using transgenic and xenograft models and tunable two-and three-dimensional substrates, we show that FNbound alpha 5 beta 1 integrin promotes tension-dependent malignant transformation through engagement of the synergy site that enhances integrin adhesion force. We determined that ligation of the synergy site of FN permits tumor cells to engage a zyxin-stabilized, vinculin-linked scaffold that facilitates nucleation of phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane to enhance phosphoinositide 3-kinase (PI3K)-dependent tumor cell invasion. The data explain why rigid collagen fibrils potentiate PI3K activation to promote malignancy and offer a perspective regarding the consistent up-regulation of alpha 5 beta 1 integrin and FN in many tumors and their correlation with cancer aggression.

• 出版日期2017-11-1
• 单位河北医科大学