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Microtubules regulate GEF-H1 in response to extracellular matrix stiffness.

ABSTRACT: 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.

SUBMITTER: Heck JN

PROVIDER: S-EPMC3386221 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Microtubules regulate GEF-H1 in response to extracellular matrix stiffness.

Heck Jessica N JN Ponik Suzanne M SM Garcia-Mendoza Maria G MG Pehlke Carolyn A CA Inman David R DR Eliceiri Kevin W KW Keely Patricia J PJ

Molecular biology of the cell 20120516 13

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 a ...[more]

PMID: 22593214

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