CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.

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 hyper-activation of AKT and sensitized cells to TGF-β1-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.

Johansson, JoelKarolinska Institutet (författare)
Ghalali, AramKarolinska Inst, Inst Environm Med, Stockholm, Sweden;Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA (författare)
Travica Asanin, SandraKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden (författare)
Santiago, AnaKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden (författare)
Rosencrantz, OskarKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden (författare)
Vincent, C. TheresaUppsala universitet,Institutionen för immunologi, genetik och patologi,Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden;Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA(Swepub:uu)thevi840 (författare)
Sollerbrant, KerstinKarolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Univ Hosp, Stockholm, Sweden (författare)
Sund, MalinUmeå universitet,Kirurgi,Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden(Swepub:umu)masu0021 (författare)
Stenius, UllaKarolinska Institutet (författare)
Fuxe, JonasKarolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden (författare)
Karolinska InstitutetKarolinska Inst, Inst Environm Med, Stockholm, Sweden;Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA (creator_code:org_t)

Ingår i:Cancer Research: American Association for Cancer Research79:1, s. 47-600008-54721538-7445

Av författaren/redakt...: Nilchian, Azadeh; Johansson, Joel; Ghalali, Aram; Travica Asanin, ...; Santiago, Ana; Rosencrantz, Osk ...; visa fler...; Vincent, C. Ther ...; Sollerbrant, Ker ...; Sund, Malin; Stenius, Ulla; Fuxe, Jonas; visa färre...

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