Regulation of fibronectin matrix assembly by activated Ras in transformed cells

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Abstract
Fibronectin extracellular matrix plays a critical role in the microenvironment of cells. Loss of this matrix frequently accompanies oncogenic transformation, allowing changes in cell growth, morphology, and tissue organization. The HT1080 human fibrosarcoma cell line is deficient in formation of fibronectin matrix fibrils but assembly can be induced by the glucocorticoid dexamethasone. Here we show that fibronectin assembly can also be restored by stimulation of alpha5beta1 integrin with activating antibody or with Mn2+ suggesting that integrin activity is reduced in these cells. While dexamethasone promoted actin stress fiber formation, actin filaments remained cortical following Mn2+ treatment showing that the dexamethasone effect is not due solely to cytoskeletal changes. HT1080 cells have one activated allele of N-ras and PD98059 inhibition of signaling from Ras through ERK increased fibronectin matrix accumulation. Conversely, the p38 MAP kinase inhibitor SB203580 blocked induction of matrix and increased ERK phosphorylation. Thus, two MAP kinase pathways contribute to the control of integrin-mediated fibronectin assembly. ERK activity and fibronectin assembly were linked in three different ras-transformed cell lines but not in SV40- or RSV-transformed cells indicating that oncogenic Ras uses a distinct mechanism to down-regulate cell-fibronectin interactions.