Regulation of ErbB2 localization and function in breast cancer cells by ERM proteins

// Nagham Asp 1, 2, 3 , Audun Kvalvaag 1, 2 , Kirsten Sandvig 1, 2, 4 , Sascha Pust 1, 2 1 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway 2 Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway 3 Current address: Department of Molecular Medicine, Division of Biochemistry, University of Oslo, 0379 Oslo, Norway 4 Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0379 Oslo, Norway Correspondence to: Sascha Pust, e-mail: sascha.pust@rr-research.no Keywords: ezrin, radixin, breast cancer, ErbB receptor tyrosine kinsases Received: September 04, 2015      Accepted: March 10, 2016      Published: March 23, 2016 ABSTRACT The ERM protein family is implicated in processes such as signal transduction, protein trafficking, cell proliferation and migration. Consequently, dysregulation of ERM proteins has been described to correlate with carcinogenesis of different cancer types. However, the underlying mechanisms are poorly understood. Here, we demonstrate a novel functional interaction between ERM proteins and the ErbB2 receptor tyrosine kinase in breast cancer cells. We show that the ERM proteins ezrin and radixin are associated with ErbB2 receptors at the plasma membrane, and depletion or functional inhibition of ERM proteins destabilizes the interaction of ErbB2 with ErbB3, Hsp90 and Ebp50. Accompanied by the dissociation of this protein complex, binding of ErbB2 to the ubiquitin-ligase c-Cbl is increased, and ErbB2 becomes dephosphorylated, ubiquitinated and internalized. Furthermore, signaling via Akt- and Erk-mediated pathways is impaired upon ERM inhibition. Finally, interference with ERM functionality leads to receptor degradation and reduced cellular levels of ErbB2 and ErbB3 receptors in breast cancer cells.