EWI2 Prevents Egfr From Clustering and Endocytosis to Reduce Tumor Cell Movement and Proliferation

Authors

Chenying Fu
Jie Wang
Sandeep Pallikkuth
Yingjun Ding
Junxiong Chen
Jonathan D Wren
Yuchao Yang
Kwong-Kwok Wong
Hiroyasu Kameyama
Muralidharan Jayaraman
Anupama Munshi
Takemi Tanaka
Keith A Lidke
Xin A Zhang

Publication Date

6-30-2022

Journal

Cellular and Molecular Life Sciences

Abstract

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate faster for better tumor formation. Inhibition of EGFR or Erk kinase can abrogate the cancer cell phenotypes resulting from EWI2 removal. Thus, to inhibit cancer cells, EWI2 prevents EGFR from clustering and endocytosis to restrain its activation and signaling.

Keywords

Antigens, CD, Cell Line, Tumor, Cell Movement, Cell Proliferation, Endocytosis, Epithelial-Mesenchymal Transition, ErbB Receptors, Humans, Integrins, Membrane Proteins, Neoplasms, And integrin, Clathrin-mediated endocytosis, Epithelial-to-mesenchymal transition, MAPK signaling, Membrane spatial heterogeneity

DOI

10.1007/s00018-022-04417-9

PMID

35773608

PMCID

PMC10428948

PubMedCentral® Posted Date

6-30-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes