Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jan 20:9:828673.
doi: 10.3389/fcell.2021.828673. eCollection 2021.

The Cross-Talk Between EGFR and E-Cadherin

Miguel Ramírez Moreno  1 , Natalia A Bulgakova  1
Affiliations
Review

The Cross-Talk Between EGFR and E-Cadherin

Miguel Ramírez Moreno et al. Front Cell Dev Biol. .

Abstract

Epidermal growth factor receptor (EGFR) and adhesion protein E-cadherin are major regulators of proliferation and differentiation in epithelial cells. Consistently, defects in both EGFR and E-cadherin-mediated intercellular adhesion are linked to various malignancies. These defects in either are further exacerbated by the reciprocal interactions between the two transmembrane proteins. On the one hand, EGFR can destabilize E-cadherin adhesion by increasing E-cadherin endocytosis, modifying its interactions with cytoskeleton and decreasing its expression, thus promoting tumorigenesis. On the other hand, E-cadherin regulates EGFR localization and tunes its activity. As a result, loss and mutations of E-cadherin promote cancer cell invasion due to uncontrolled activation of EGFR, which displays enhanced surface motility and changes in endocytosis. In this minireview, we discuss the molecular and cellular mechanisms of the cross-talk between E-cadherin and EGFR, highlighting emerging evidence for the role of endocytosis in this feedback, as well as its relevance to tissue morphogenesis, homeostasis and cancer progression.

Keywords: adhesion; cancer; epithelia; morphogenesis; signalling.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of mechanisms controlling EGFR and E-cadherin endocytosis. (A,B) – Summary of EGFR (A) and E-cadherin (B) regulation. Ligand-induced activation and dimerization of EGFR (A) trigger endocytosis of the receptor. The clathrin-mediated endocytosis is followed by recycling of the receptor and comprises most of the endocytic events, whereas clathrin-independent endocytosis, including caveolae, leads to EGFR degradation and is promoted upon a certain threshold of EGFR activation. Ubiquitination by Cbls ubiquitin ligases serves as a key cue for EGFR degradation and is modulated by EGFR phosphorylation. Levels of E-cadherin at the plasma membrane (B) are regulated by endocytosis, which is modulated by E-cadherin interactions with its binding partners. β-catenin (β-cat) helps retain E-cadherin at the membrane, whereas p120-catenin (p120ctn) prevents E-cadherin endocytosis for degradation but promotes its recycling. Both clathrin-mediated and independent pathways can be followed by either E-cadherin recycling or degradation, but the latter depends on E-cadherin ubiquitination by the ubiquitin ligase Hakai and potentially others. E-cadherin membrane presentation also regulates own gene (E-CAD) expression. Dynamics of both E-cadherin and EGFR is also regulated by glycosylation of their extracellular domains.
FIGURE 2
FIGURE 2
Interactions between EGFR and E-cadherin. (A) – Summary of the known effects of EGFR activation on E-cadherin. EGFR signalling downregulates E-cadherin (E-CAD) gene expression via the transcriptional repressors SNAIL and SLUG. By promoting phosphorylation, it also destabilizes membrane E-cadherin by reducing its affinity with β-catenin and the subsequent connection to the actin cytoskeleton as well as alters interactions between p120-catenin with RhoA. Additionally, EGFR signalling increases E-cadherin endocytosis by blocking Caveolin-1 activity, a negative regulator of the EGFR pathway itself, and promotes processing of E-cadherin into soluble E-cadherin (sE-cad) through activation of the Matrix Metalloproteinases (MMPs) 2 and 9. Grey dashed lines indicate protein binding. (B) – Summary of the known effects of E-cadherin on EGFR. E-cadherin stabilizes EGFR at the membrane, blocks its activation by EGF and reduces its internalization. Through STAT3 and RanBP6, E-cadherin represses EGFR gene expression. Additionally, sE-Cad is an agonistic ligand of EGFR, and therefore E-cadherin cleavage, which is promoted by EGFR activity, positively regulates EGFR signalling. (C) – Model of the feedback mechanism between EGFR activity and E-cadherin; the negative feedback loop between the two leads to stable EGFR activation and loss of E-cadherin in cancer cells. Gray arrows indicate unknown mechanisms by which both transmembrane proteins coexist and fine-tune each other in normal tissue during development and homeostasis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Advedissian T., Proux-Gillardeaux V., Nkosi R., Peyret G., Nguyen T., Poirier F., et al. (2017). E-cadherin Dynamics Is Regulated by Galectin-7 at Epithelial Cell Surface. Sci. Rep. 7, 17086. 10.1038/s41598-017-17332-y - DOI - PMC - PubMed
    1. Alemà S., Salvatore A. M. (2007). p120 Catenin and Phosphorylation: Mechanisms and Traits of an Unresolved Issue. Biochim. Biophys. Acta (Bba) - Mol. Cel Res. 1773, 47–58. 10.1016/j.bbamcr.2006.06.001 - DOI - PubMed
    1. Bae G.-Y., Choi S.-J., Lee J.-S., Jo J., Lee J., Kim J., et al. (2013). Loss of E-Cadherin Activates EGFR-MEK/ERK Signaling, Which Promotes Invasion via the ZEB1/MMP2 axis in Non-small Cell Lung Cancer. Onco_target 4, 2512–2522. 10.18632/onco_target.1463 - DOI - PMC - PubMed
    1. Barbieri E., Di Fiore P. P., Sigismund S. (2016). Endocytic Control of Signaling at the Plasma Membrane. Curr. Opin. Cel Biol. 39, 21–27. 10.1016/j.ceb.2016.01.012 - DOI - PubMed
    1. Bartlett J., Langdon S., Simpson B., Stewart M., Katsaros D., Sismondi P., et al. (1996). The Prognostic Value of Epidermal Growth Factor Receptor mRNA Expression in Primary Ovarian Cancer. Br. J. Cancer 73, 301–306. 10.1038/bjc.1996.53 - DOI - PMC - PubMed
  NODES
INTERN 1
twitter 2