Rsu1-dependent control of PTEN expression is regulated via ATF2 and cJun
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The Rsu1 protein contributes to cell adhesion and migration via its association with the adaptor complex of Integrin linked kinase (ILK), PINCH, and Parvin (IPP), which binds to the cytoplasmic domain of β1 integrins joining integrins to the actin cytoskeleton. Rsu1 binding to PINCH in the IPP complex is required for EGF-induced adhesion, spreading and migration in MCF10A mammary epithelial cells. In addition, Rsu1 expression inhibits Jun kinase but is necessary for the activation of MKK4 and p38 Map kinase signaling essential for migration in MCF10A cells. The data reported here examines the links between MKK4-p38-ATF2 signaling and AKT regulation in MCF10A cells. Ectopic Rsu1 inhibited AKT1 phosphorylation while Rsu1 depletion induced AKT activation and AKT1 phosphorylation of MKK4 on serine 80, blocking MKK4 activity. Rsu1 depletion also reduced the RNA for lipid phosphatase PTEN thus implicating PTEN in modulating levels of activated AKT in these conditions. ChIP analysis of the PTEN promoter revealed that Rsu1 depletion prevented binding of ATF2 to a positive regulatory site in the PTEN promoter and the enhanced binding of cJun to a negatively regulatory PTEN promoter site. These results demonstrate a mechanism by which Rsu1 adhesion signaling alters the balance between MKK4-p38-ATF2 and cJun activation thus altering PTEN expression in MCF10A cells.
KeywordsRsu1 MKK4: ATF2: PTEN Adhesion Migration
The following funding agencies provided support: the Murtha Cancer Center at Walter Reed National Military Medical Center through Uniformed Services University under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine (to MLC) and W81XWH-10-1-0024 from the Congressionally Directed Medical Research Breast Cancer Program (pre-doctoral fellowship to RG-N).
Compliance with ethical standards
The opinions expressed here are those of the authors and should not be construed as official policy or reflecting the views of the Uniformed Services University of the Health Sciences or the Department of the Navy, Army, or the Department of Defense. In addition, any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the US Government.
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