Journal
ONCOTARGET
Volume 7, Issue 18, Pages 25443-25460Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8327
Keywords
ezrin; radixin; breast cancer; ErbB receptor tyrosine kinsases
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Funding
- South-Eastern Norway Regional Health Authority (Helse Sor-Ost)
- Norwegian Research Council through its Centres of Excellence [179571]
- Norwegian Cancer Society
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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.
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