Abstract
Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here, we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyperactivation of AKT and sensitized cells to TGFβ1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer. SIGNIFICANCE: The tight junction protein CXADR controls epithelial-mesenchymal plasticity in breast cancer by stabilizing the AKT regulators PTEN and PHLPP2.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/1/47/F1.large.jpg.
Highlights
Tight junctions (TJ) are multiprotein complexes located at apical–lateral borders in epithelial cells
The results showed that pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2), and PTEN colocalized with coxsackie and adenovirus receptor (CXADR) at TJs in EpRas cells, and in EpH4 cells (Fig. 3A; Supplementary Fig. S3A)
PHLPP2 and PTEN localized mostly to the cytoplasm in EpXT cells, in which TJ staining for CXADR and membrane-associated guanylate kinase inverted (MAGI)-1 was diffuse and discontinuous (Fig. 3B). These results showed that PHLPP2 and PTEN colocalize with CXADR at TJs in mammary epithelial cells
Summary
Tight junctions (TJ) are multiprotein complexes located at apical–lateral borders in epithelial cells. They control paracellular permeability and regulate epithelial proliferation, polarization, and differentiation [1]. TJs are composed of transmembrane proteins including MARVEL domain proteins (i.e., occludin), claudins, and Ig-type proteins (i.e., JAM-A, CXADR), which form. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Johansson: Cancer Research UK Beatson Institute, Glasgow, United Kingdom; and current address for A. Ghalali: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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