Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosis
Open Access
- 1 September 2008
- journal article
- review article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 12 (5a), 1527-1534
- https://doi.org/10.1111/j.1582-4934.2008.00298.x
Abstract
The epidermal growth factor receptor (EGFR) and other members of the EGFR/ErbB receptor family of receptor tyrosine kinases (RTKs) are important regulators of proliferation, angiogenesis, migration, tumorigenesis and metastasis. Overexpression, mutations, deletions and production of autocrine ligands contribute to aberrant activation of the ErbB proteins. The signalling output from EGFR is complicated given that other ErbB proteins are often additionally expressed and activated in the same cell, resulting in formation of homo-and/or heterodimers. In particular, association of EGFR with ErbB2 prevents its down-regulation, underscoring the importance of the cellular background for EGFR effects. Signalling from ErbB proteins can either be terminated by dissociation of ligand resulting in dephosphorylation, or blunted by degradation of the receptors. Although proteasomal targeting of ErbB proteins has been described, lysosomal degradation upon ligand-induced endocytosis seems to play the major role in EGFR down-regulation. Preclinical and clinical data have demonstrated that EGFR is a central player in cancer, especially in carcinomas, some brain tumours and in non-small cell lung cancer. Such studies have further validated EGFR as an important molecular target in cancer treatment. This review focuses on mechanisms involved in ligand-induced EGFR activation and endocytic down-regulation. A better understanding of EGFR biology should allow development of more tumour-selective therapeutic approaches targeting EGFR-induced signalling.Keywords
This publication has 77 references indexed in Scilit:
- EGF receptor ubiquitination is not necessary for its internalizationProceedings of the National Academy of Sciences of the United States of America, 2007
- Plasticity of Polyubiquitin Recognition as Lysosomal Targeting Signals by the Endosomal Sorting MachineryMolecular Biology of the Cell, 2007
- p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapyThe EMBO Journal, 2006
- EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteinsOncogene, 2006
- ERBB receptors and cancer: the complexity of targeted inhibitorsNature Reviews Cancer, 2005
- Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complexCancer Cell, 2004
- Clathrin-mediated endocytosis in AP-2–depleted cellsThe Journal of cell biology, 2003
- EGF Activates Its Receptor by Removing Interactions that Autoinhibit Ectodomain DimerizationMolecular Cell, 2003
- A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signalingThe EMBO Journal, 2002
- NEW EMBO MEMBERS' REVIEW: The ErbB signaling network: receptor heterodimerization in development and cancerThe EMBO Journal, 2000