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Published on: May 19, 2016
Regulation of fibronectin matrix assembly by activated Ras in transformed cells
K A Brenner1, S A Corbett, J E Schwarzbauer
1Department of Molecular Biology, Princeton University, New Jersey 08544, USA.
Oncogene
|August 2, 2000
Summary
Fibronectin matrix assembly, crucial for cell behavior, can be restored in fibrosarcoma cells by targeting alpha5beta1 integrin or inhibiting ERK signaling. Oncogenic Ras specifically down-regulates cell-fibronectin interactions.
Area of Science:
- Cell Biology
- Extracellular Matrix
- Integrative Biology
Background:
- Fibronectin extracellular matrix is vital for cellular microenvironment and tissue organization.
- Loss of fibronectin matrix is common in oncogenic transformation, altering cell growth and morphology.
- HT1080 fibrosarcoma cells exhibit deficient fibronectin matrix formation, but assembly can be induced.
Purpose of the Study:
- To investigate mechanisms restoring fibronectin matrix assembly in HT1080 cells.
- To determine the role of alpha5beta1 integrin activity and signaling pathways in fibronectin matrix formation.
- To elucidate the specific role of oncogenic Ras in down-regulating cell-fibronectin interactions.
Main Methods:
- Stimulation of alpha5beta1 integrin using activating antibody or Mn2+.
- Treatment with dexamethasone to induce fibronectin assembly and actin stress fibers.
- Inhibition of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways using PD98059 and SB203580, respectively.
- Analysis of fibronectin matrix accumulation and actin filament organization.
Main Results:
- Fibronectin assembly in HT1080 cells was restored by alpha5beta1 integrin stimulation, suggesting reduced integrin activity.
- Dexamethasone induced actin stress fibers, while Mn2+ treatment resulted in cortical actin.
- Inhibition of ERK signaling increased fibronectin matrix accumulation, whereas p38 MAPK inhibition blocked matrix induction and increased ERK phosphorylation.
- ERK activity was linked to fibronectin assembly in ras-transformed cells but not in SV40- or RSV-transformed cells.
Conclusions:
- Integrin activity and specific MAP kinase pathways (ERK and p38) are critical regulators of fibronectin assembly.
- Oncogenic Ras employs a distinct mechanism to down-regulate cell-fibronectin interactions, involving ERK signaling.
- Restoring fibronectin matrix assembly may be a therapeutic strategy for cancers with altered extracellular matrix.
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