Microtubules regulate GEF-H1 in response to extracellular matrix stiffness
Open accessAbstract
Breast epithelial cells sense the stiffness of the extracellular matrix through Rho-mediated contractility. In turn, matrix stiffness regulates RhoA activity. However, the upstream signaling mechanisms are poorly defined. Here we demonstrate that the Rho exchange factor GEF-H1 mediates RhoA activation in response to extracellular matrix stiffness. We demonstrate the novel finding that microtubule stability is diminished by a stiff three-dimensional (3D) extracellular matrix, which leads to the activation of GEF-H1. Surprisingly, activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway did not contribute to stiffness-induced GEF-H1 activation. Loss of GEF-H1 decreases cell contraction of and invasion through 3D matrices. These data support a model in which matrix stiffness regulates RhoA through microtubule destabilization and the subsequent release and activation of GEF-H1.
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GEF-H1 can control RhoA activity in response to local changes in the density of dynamic microtubules near the cell margin, e.g., to promote cell invasion or trigger cell retraction and help migrating dendritic cells maintain coherence.
“In this way, GEF-H1 can control RhoA activity in response to local changes in the density of dynamic microtubules near the cell margin, for example, to promote cell invasion into a dense matrix or trigger cell retraction and help cells with long and elaborate protrusions, such as migrating dendritic cells, to maintain their coherence 21,24-26 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [24]
The Introduction and Results report that microtubules participate in GEF-H1–dependent RhoA activation in response to matrix stiffness, and that GEF-H1 knockdown inhibits breast carcinoma cell invasion through stiff gels. The paper does not establish that local changes in dynamic microtubule density near the cell margin trigger retraction or help migrating dendritic cells maintain coherence (no page numbers are available in our copy). (LLM, conf=0.86)
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Self-citation
- Authors
- Heck, J. N., Ponik, S. M., Garcia-Mendoza, M. G., Pehlke, C. A., Inman, D. R., Eliceiri, K. W., & Keely, P. J.
- Affiliations
- University of Wisconsin System (US)
- Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53706
- University of Wisconsin–Madison (US)
- Corresponding author
- Heck, Jessica N.
- Keely, Patricia J.
- Venue
- Molecular Biology of the Cell
- Published
- 2012-07
- Volume
- 23
- Issue
- 13
- Pages
- 2583-2592
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC3386221
- OpenAlex
- W2160532246
- Cited by
- 96
- References
- 51
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 5
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (T32 GM008688)
- National Institutes of Health
- National Cancer Institute (R01CA142833, R01CA114462, P30CA014520)
- National Institute of General Medical Sciences (T32GM008688)
- U.S. National Library of Medicine (T15LM007359)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- GEF-H1, RhoA activation, extracellular matrix stiffness, microtubule stability, microtubule destabilization, breast epithelial cells, cell contractility, cell invasion, MEK/ERK signaling, mechanotransduction
- MeSH terms
- Animals, Biomechanical Phenomena, Cell Movement, Cells, Cultured, Epithelial Cells, Extracellular Matrix, Humans, Mammary Glands, Animal, Microtubules, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, MAP Kinase Signaling System, RNA Interference, Extracellular Signal-Regulated MAP Kinases, Mice, Protein Stability, Gene Knockdown Techniques, Rho Guanine Nucleotide Exchange Factors
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