Microtubules regulate GEF-H1 in response to extracellular matrix stiffness
| Autor: | David R. Inman, Patricia J. Keely, Jessica N. Heck, Carolyn Pehlke, Kevin W. Eliceiri, Maria G. Garcia-Mendoza, Suzanne M. Ponik |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
musculoskeletal diseases
RHOA animal structures MAP Kinase Signaling System macromolecular substances Microtubules Extracellular matrix Contractility 03 medical and health sciences Mice 0302 clinical medicine Mammary Glands Animal Microtubule Cell Movement Extracellular Animals Guanine Nucleotide Exchange Factors Humans Protein kinase A Extracellular Signal-Regulated MAP Kinases Molecular Biology Cells Cultured 030304 developmental biology 0303 health sciences biology Kinase Protein Stability technology industry and agriculture Epithelial Cells Cell Biology Articles equipment and supplies Signaling Cell biology Biomechanical Phenomena Extracellular Matrix 030220 oncology & carcinogenesis Gene Knockdown Techniques biology.protein RNA Interference Guanine nucleotide exchange factor rhoA GTP-Binding Protein Rho Guanine Nucleotide Exchange Factors |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | Rho GTPase plays a role in mechanosensing, and breast epithelial cells sense the stiffness of the extracellular matrix through Rho-mediated contractility. Microtubule stability is reduced by a stiff matrix, which leads to the activation of the Rho exchange factor GEF-H1. 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. |
| Databáze: | OpenAIRE |
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