期刊
CELL CYCLE
卷 9, 期 21, 页码 4315-4322出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.21.13578
关键词
laminin; PI3K-Rac1 pathway; polarity; sustained STAT5 activation
类别
资金
- US Department of Energy, the Office of Biological and Environmental Research [DE-AC02-05CH1123]
- Office of Health and Environmental Research Health Effects Division [03-76SF00098]
- National Cancer Institute [R01CA064786, U54CA126552, U54CA112970, R01CA057621]
- US Department of Defense [W81XWH0810736, W81XWH0510338]
- Canadian Institutes of Health Research [DAMD17-02-1-0441, W81XWH0410581]
- U.S. Department of Defense (DOD) [W81XWH0410581, W81XWH0510338] Funding Source: U.S. Department of Defense (DOD)
Extracellular matrix (ECM) is a key regulator of tissue morphogenesis and functional differentiation in the mammary gland. We showed recently that laminin-111 (LN1) together with prolactin induces beta-casein expression in mammary epithelial cells (MECs) by sustaining STAT5 activation. Others have shown that Rac1 is required for integrin-mediated STAT5 activation, but molecules upstream of Rac1 remain to be elucidated. Here, we show that exposure to three-dimensional (3D) laminin-rich ECM (LrECM) gels changes the localization of phosphoinositide 3-kinase (PI3K) in MECs from diffuse to basal accompanied with the activation of PI3K-Rac1 signaling pathway. We show by co-immunoprecipitation that Rac1 associates with STAT5, and that LrECM treatment enhances this interaction. Blocking PI3K with LY294002 inhibits LrECM-dependent Rac1 activation, attenuates sustained STAT5 phosphorylation and blocks beta-casein gene transcription. These results indicate that PI3K is a key mediator of the LN1-induced signaling cascade which controls the activity of transcription factors essential for tissue-specific gene expression.
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