The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities
Introduction
The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases lies at the head of a complex signal transduction cascade that modulates cell proliferation, survival, adhesion, migration and differentiation. While growth-factor-induced EGFR signalling is essential for many normal morphogenic processes and involved in numerous additional cellular responses, the aberrant activity of members of this receptor family has been shown to play a key role in the development and growth of tumour cells. This review highlights the complexity of the highly conserved EGFR signalling module, its central role in a diverse array of biological processes and the multiple mechanisms that modulate the strength and duration of EGFR signalling.
The EGFR family comprises four distinct receptors: EGFR/ErbB-1, HER2/ErbB-2, HER3/ErbB-3 and HER4/ErbB-4. These transmembrane receptors are composed of an extracellular ligand-binding domain and a cytoplasmic region with enzymatic activity [1]. This structure enables signals to be transmitted across the plasma membrane where they activate gene expression and ultimately induce cellular responses such as proliferation. The signal-transducing tyrosine kinase activity of the EGFR and related receptors is inactive when the receptors are in isolation. A number of different ligands, including EGF-like molecules, transforming growth factor (TGF)-α and neuregulins, activate the receptor by binding to the extracellular domain and inducing the formation of receptor homodimers or heterodimers (Fig. 1). Tyrosine residues on one receptor are presumably cross-phosphorylated by the other member of the receptor pair and then form docking sites for signalling complexes composed of cytoplasmic enzymes and adapter proteins. The subsequent dissociation of these signalling complexes releases activated effector and adapter proteins into the cytoplasm where they stimulate many different signal transduction cascades, such as the mitogen-activated protein kinase (MAPK) pathway, phosphoinositol kinase, the anti-apoptotic kinase Akt and several transcriptional regulators. Finally, the EGFR signal is inactivated primarily through endocytosis of the receptor–ligand complex. The contents of the resulting endosomes are then either degraded or recycled to the cell surface (reviewed in Ref. [2]).
In this signalling network, the major partner of EGFR is HER2 [4], and several mechanisms contribute to make HER2 heterodimeric signals particularly potent. First, activated heterodimeric complexes containing HER2 are more stable at the cell surface than are complexes containing other EGFR family members [5]. Although HER2 does not act as a receptor for EGF, it can decrease the rate of ligand dissociation from the cognate receptor, EGFR [6]. This results in stronger and more prolonged activation of the EGFR signalling network. Heterodimers containing HER2 also remain at the cell surface for a longer period of time, undergoing endocytosis at a lower rate than do EGFR homodimers. Furthermore, once the activated complex is internalised, HER2–EGFR heterodimers are targeted for recycling, while EGFR homodimers are destined for degradation. The recycling pathway returns receptors to the cell surface, ready for another cycle of activation and augments growth-factor signalling [5].
Section snippets
Morphogenesis—a conserved function of the EGFR signalling network
The EGFR signalling module has been highly conserved throughout the course of evolution. The primordial signalling unit found in the nematode Caenorhabditis elegans consists of a single EGF-like ligand known as LIN-3 and one receptor protein called LET-23 7, 8 (Fig. 2). In this organism, the EGFR network plays a central developmental role, determining the fate of several types of cells. The first function identified for this ancient signalling module was vulval induction, which occurs when the
EGFR signal transduction—a complex network
EGFR ligands and receptors clearly play critical roles in many aspects of morphogenesis. However, the complexity of this signal transduction system in most cases precludes tracing a signalling event from its initiation at the cell surface with a ligand and receptor dimer through particular adapter and effector proteins to culminate in gene activation and a cellular response. Instead, the EGFR signalling module is perhaps best thought of in terms of a richly layered network (Fig. 3). The first
Oncogenic viruses harness EGFR signalling
Another avenue of research that has highlighted the importance of EGFR signalling is the study of viral oncogenes. Viruses exploit this signalling network in many different ways, altering both receptor tyrosine kinase activity and gene expression (Fig. 4). For example, hepatitis B virus and Epstein–Barr virus both activate EGFR expression during the invasion process. In contrast, avian erythoblastosis virus encodes a truncated form of EGFR which is constitutively active, while the human
Internalised ligand–receptor complexes are recycled or degraded
During signal termination, activated EGFR complexes are endocytosed in clatherin-coated pits. Two distinct processes have been identified that determine the fate of the internalised receptors (Fig. 5). The first of these processes involves a ubiquitin ligase known as Cbl. Recruitment of Cbl to ligand–receptor complexes in early endosomes targets receptors for lysosomal degradation by promoting receptor ubiquitination. In the absence of Cbl or when v-Cbl, the viral, oncogenic form of Cbl, is
Conclusion
The EGFR family of growth-factor receptors form part of a complex signal transduction network which is at the centre of many important cellular responses. This evolutionarily conserved signalling module plays a crucial role in the morphogenesis of many different organisms and also mediates a variety of cellular processes, including cell proliferation, migration, survival and adhesion. Decades of research have revealed multiple mechanisms that modulate the strength and duration of EGFR signals
References (25)
- et al.
Signal transduction by receptors with tyrosine kinase activity
Cell
(1990) Molecules in focusEGF receptor
Int. J. Biochem. Cell. Biol.
(1999)- et al.
Transmembrane signalling receptors for cytokines and growth factors
Curr. Opin. Struct. Biol.
(1991) - et al.
A thousand and one roles for the Drosophila EGF receptor
Trends Genet.
(1997) - et al.
Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation
Cell
(1993) - et al.
TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice
Cell
(1993) - et al.
The EGFR as a target for viral oncoproteins
Trends. Microbiol.
(1999) - et al.
Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1
Mol. Cell.
(1999) - et al.
A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor
Mol. Cell. Biol.
(1996) - et al.
Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers
Embo. J.
(1998)
ErbB-2 is a common auxiliary subunit of NDF and EGF receptorsimplications for breast cancer
Embo. J.
The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily
Nature
Cited by (1401)
Development and validation of pharmacokinetics assays for a novel HER2-targeting antibody-drug conjugate (SHR-A1201): Application to its dose-escalation pharmacokinetic study
2024, Journal of Pharmaceutical and Biomedical AnalysisAnnual review of PROTAC degraders as anticancer agents in 2022
2024, European Journal of Medicinal ChemistryTiron ameliorates acetic acid-induced colitis in rats: Role of TGF-β/EGFR/PI3K/NF-κB signaling pathway
2024, International ImmunopharmacologyEntanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders
2023, Biochimica et Biophysica Acta - Gene Regulatory MechanismsEmerging insights into mechanisms of trastuzumab resistance in HER2-positive cancers
2023, International ImmunopharmacologyThe role of interferon-gamma and its receptors in gastrointestinal cancers
2023, Pathology Research and Practice