Microtubules regulate GEF-H1 in response to extracellular matrix stiffness

作者：Heck Jessica N; Ponik Suzanne M; Garcia Mendoza Maria G; Pehlke Carolyn A; Inman David R; Eliceiri Kevin W; Keely Patricia J^*

来源：Molecular Biology of the Cell, 2012, 23(13): 2583-2592.

DOI：10.1091/mbc.E11-10-0876

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.

• 出版日期2012-7-1