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

Nagham Asp,Kirsten Sandvig,Audun Kvalvaag,Sascha Pust

doi:10.18632/oncotarget.8327

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.

Highlights

The members of the ERM protein family are scaffolding proteins at the plasma membrane and act as functional linkers between the membrane and the actin cytoskeleton [1]
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, head shock protein 90 (Hsp90) and Ebp50
The ERM proteins ezrin and radixin are associated with ErbB receptors at the plasma membrane in breast cancer cells

Summary

Introduction

The members of the ERM protein family (ezrin, radixin and moesin) are scaffolding proteins at the plasma membrane and act as functional linkers between the membrane and the actin cytoskeleton [1]. The prominent localization of ERM proteins at the plasma membrane is reflected by their structural and functional involvement in a multitude of cellular processes. Activation of ERM proteins by binding to PI(4, 5) P2 and phosphorylation has been shown to be a prerequisite for activation of different signaling pathways [5,6,7]. The interaction between ERM proteins and transmembrane receptors, including receptor tyrosine kinases (RTKs), is required for various signal transduction pathways [8]. ERM proteins have been described to be associated with ErbB receptor tyrosine kinases (RTKs) and are considered to have a regulatory role in RTK function [16,17,18,19]. The mechanistic function of ERM proteins in the regulation of ErbB2 receptor tyrosine kinases and carcinogenesis is not yet understood

Methods

Results

Conclusion