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TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.

Publication ,  Journal Article
Osborne, LD; Li, GZ; How, T; O'Brien, ET; Blobe, GC; Superfine, R; Mythreye, K
Published in: Mol Biol Cell
November 5, 2014

Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell-cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)-induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5-enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β-induced EMT.

Duke Scholars

Published In

Mol Biol Cell

DOI

EISSN

1939-4586

Publication Date

November 5, 2014

Volume

25

Issue

22

Start / End Page

3528 / 3540

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Rho Guanine Nucleotide Exchange Factors
  • Pressure
  • Neoplasm Invasiveness
  • Mice
  • Mechanotransduction, Cellular
  • Integrins
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Epithelial-Mesenchymal Transition
 

Citation

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ICMJE
MLA
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Osborne, L. D., Li, G. Z., How, T., O’Brien, E. T., Blobe, G. C., Superfine, R., & Mythreye, K. (2014). TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Mol Biol Cell, 25(22), 3528–3540. https://doi.org/10.1091/mbc.E14-05-1015
Osborne, Lukas D., George Z. Li, Tam How, E Tim O’Brien, Gerard C. Blobe, Richard Superfine, and Karthikeyan Mythreye. “TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.Mol Biol Cell 25, no. 22 (November 5, 2014): 3528–40. https://doi.org/10.1091/mbc.E14-05-1015.
Osborne LD, Li GZ, How T, O’Brien ET, Blobe GC, Superfine R, et al. TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Mol Biol Cell. 2014 Nov 5;25(22):3528–40.
Osborne, Lukas D., et al. “TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.Mol Biol Cell, vol. 25, no. 22, Nov. 2014, pp. 3528–40. Pubmed, doi:10.1091/mbc.E14-05-1015.
Osborne LD, Li GZ, How T, O’Brien ET, Blobe GC, Superfine R, Mythreye K. TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Mol Biol Cell. 2014 Nov 5;25(22):3528–3540.

Published In

Mol Biol Cell

DOI

EISSN

1939-4586

Publication Date

November 5, 2014

Volume

25

Issue

22

Start / End Page

3528 / 3540

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Rho Guanine Nucleotide Exchange Factors
  • Pressure
  • Neoplasm Invasiveness
  • Mice
  • Mechanotransduction, Cellular
  • Integrins
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Epithelial-Mesenchymal Transition