The RhoA-Rok-myosin II pathway is involved in extracellular matrix-mediated regulation of prolactin signaling in mammary epithelial cells

Du, Jyun-Yi; Chen, Meng-Chi; Hsu, Tsai-Ching; Wang, Jen-Hsing; Brackenbury, Lisa; Lin, Ting-Hui; Wu, Yi-Ying; Yang, Zhihong; Streuli, Charles H.; Lee, Yi-Ju

doi:10.1002/jcp.22886

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Journal article

The RhoA-Rok-myosin II pathway is involved in extracellular matrix-mediated regulation of prolactin signaling in mammary epithelial cells

Du, Jyun-Yi Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
Chen, Meng-Chi Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
Hsu, Tsai-Ching Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
Wang, Jen-Hsing Department of Obstetrics and Gynecology, Antai Tian-Sheng Memorial Hospital, Pingtung, Taiwan
Brackenbury, Lisa Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Manchester, UK
Lin, Ting-Hui Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
Wu, Yi-Ying Department of Medical Laboratory Science and Biotechnology, China Medical University and Hospital, Taichung, Taiwan
Yang, Zhihong Vascular Biology, Physiology Unit, Departement of Medicine, University of Fribourg, Switzerland
Streuli, Charles H. Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Manchester, UK
Lee, Yi-Ju Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan - Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

11.01.2012

Published in:

Journal of Cellular Physiology. - 2012, vol. 227, no. 4, p. 1553–1560

English In mammary epithelial cells (MECs), prolactin-induced signaling and gene expression requires integrin-mediated cell adhesion to basement membrane (BM). In the absence of proper cell–BM interactions, for example, culturing cells on collagen-coated plastic dishes, signal propagation is substantially impaired. Here we demonstrate that the RhoA-Rok-myosin II pathway accounts for the ineffectiveness of prolactin signaling in MECs cultured on collagen I. Under these culture conditions, the RhoA pathway is activated, leading to downregulation of prolactin receptor expression and reduced prolactin signaling. Enforced activation of RhoA in MECs cultured on BM suppresses prolactin receptor levels, and prevents prolactin-induced Stat5 tyrosine phosphorylation and β-casein expression. Overexpression of dominant negative RhoA in MECs cultured on collagen I, or inhibiting Rok activity, increases prolactin receptor expression, and enhances prolactin signaling. In addition, inhibition of myosin II ATPase activity by blebbistatin also exerts a beneficial effect on prolactin receptor expression and prolactin signaling, suggesting that tension exerted by the collagen substratum, in collaboration with the RhoA-Rok-myosin II pathway, contributes to the failure of prolactin signaling. Furthermore, MECs cultured on laminin-coated plastic have similar morphology and response to prolactin as those cultured on collagen I. They display high levels of RhoA activity and are inefficient in prolactin signaling, stressing the importance of matrix stiffness in signal transduction. Our results reveal that RhoA has a central role in determining the fate decisions of MECs in response to cell–matrix interactions.

Faculty

Faculté des sciences et de médecine

Department

Département de Médecine

Language