Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosis

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.

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(A) EGFR dimerization upon ligand binding triggers auto-phosphorylation (P) and ubiquitination (Ub) of its cytoplasmic domain. This causes recruitment of effector proteins, like Grb2, Src and Cbl. (B) Intracellular route leading EGFR to down-regulation by lysosomal degradation. PM: plasma membrane, CCP: clathrin-coated pit, MVB: multivesicular body.

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Tentative model of molecular interactions promoting regulated entry of EGFR into clathrin-coated pits (CCP). Initial recruitment of ubiquitinated EGFR to Eps15 at the rim of CCPs allows for its transfer to Epsin present in the entire CCP curvature. Green circles represent ubiquitin.

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Molecular interactions regulating endosomal sorting of EGFR to the degradative pathway. At the limiting membrane of the late endosome/MVB, ubiquitinated EGFR interacts with ESCRT 0-III. This results into clustering to inward budding domains, eventually generating the inner vesicles of MVBs and degradation. Alternatively, EGFR can be deubiquitinated by de-ubiquiting enzymes (deubi) and recycled back to the plasma membrane. ESCRT complexes and ubiquitin are removed and recycled to the cytosolic pool before internal vesicles are formed.