TY - JOUR
T1 - Ligand-independent activation of c-Met by fibronectin and α5 Β1-integrin regulates ovarian cancer invasion and metastasis
AU - Mitra, A. K.
AU - Sawada, K.
AU - Tiwari, P.
AU - Mui, K.
AU - Gwin, K.
AU - Lengyel, E.
N1 - Funding Information:
We thank Dr Alan Horwitz, Department of Cell Biology, University of Virginia School of Medicine for providing us with the FAK constructs. We thank Gail Isenberg for critically reviewing the manuscript. We appreciate the inputs of Dr Vinay Bhaskar and Dr Vanitha Ramakrishnan during the initial part of the project. Funding: Ernst Lengyel holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and is supported by grants from the Ovarian Cancer Research Fund (Liz Tilberis Scholars Program), and the NCI (RO1 CA111882).
PY - 2011/3/31
Y1 - 2011/3/31
N2 - The role of the fibronectin receptor, α 5 Β 1-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α 5 Β 1-integrin led to a direct association of α 5-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α 5 Β 1-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α 5 Β 1-integrin inhibition on tumor cell invasion, indicating that α 5 Β 1-integrin is upstream of c-Met, Src and FAK. Inhibition of α 5 Β 1-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α 5 Β 1-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α 5 Β 1-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.
AB - The role of the fibronectin receptor, α 5 Β 1-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α 5 Β 1-integrin led to a direct association of α 5-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α 5 Β 1-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α 5 Β 1-integrin inhibition on tumor cell invasion, indicating that α 5 Β 1-integrin is upstream of c-Met, Src and FAK. Inhibition of α 5 Β 1-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α 5 Β 1-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α 5 Β 1-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.
KW - FAK
KW - Src
KW - c-Met
KW - fibronectin
KW - ovarian cancer
KW - αβ-integrin
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U2 - 10.1038/onc.2010.532
DO - 10.1038/onc.2010.532
M3 - Article
C2 - 21119598
AN - SCOPUS:79953220086
SN - 0950-9232
VL - 30
SP - 1566
EP - 1576
JO - Oncogene
JF - Oncogene
IS - 13
ER -