The laboratory of Stanley Cohen discovered in 1980 that addition of EGF to the culture medium of human epidermoid carcinoma (A431) cells yields massive tyrosine phosphorylation, similarly to cells infected with oncogenic viruses [1
]. Although not known at the time, it was speculated by Stanley Cohen and colleagues, that the EGF-receptor (EGFR) and the observed kinase activity are present in the same molecule [2
]. In the past thirty years we have learned a great deal about the structure of growth factor receptors, their intrinsic ligand recognition and kinase functions, and the cellular outcomes of their activation. Upon their ligand-induced dimerization, growth factor receptors initiate a vast array of cell signaling pathways (), with profound effects on cell fate decisions such as proliferation, cell lineage determination and differentiation, migration and even cell death. Due to their importance, these mechanisms evolved to be tightly regulated and robust. One of the best-studied examples for such mechanisms is the EGFR family, also called the ErbB family, which belongs to the super-family of receptor tyrosine kinases (RTKs). These plasma membrane bound receptors are mainly composed of an extracellular ligand-binding, and a single trans-membrane domain, followed by an intracellular tyrosine kinase domain and a non-catalytic carboxyl terminal tail. This configuration allows extracellular signals to be relayed into the cell, and to be interpreted in order to evoke a proper response: Activation is achieved following a series of processes starting with the interaction between the ligand and the ligand-binding domain of the receptor. This binding induces a structural change which exposes an otherwise tethered dimerization arm [3
], leading to coupling of two receptor molecules. Now, closer together in the correct orientation, the two kinase domains interact asymmetrically, while one kinase acts as an activator and the second being activated [4
]. The activated kinase phosphorylates tyrosine residues located at the receptor’s tail, which then act as docking sites for adaptor molecules linking the receptor to its downstream signaling pathways ().
Activation mechanisms and signaling pathways engaged by EGFR
During evolution, the single nematode ErbB receptor, Let-23, underwent two duplication events and subsequent incorporation of further mutations, resulting in a family of four members in mammals [5
], which seem to be similar at the first glance, but were discovered to be profoundly different [6
]. While ligand binding activates the kinase domain of EGFR/ErbB-1, as well as ErbB4, ErbB-2 has no compatible ligand and is kept in a constitutively active state [8
]. On the other hand, ErbB-3 maintained its ligand-binding capacity, but its kinase domain was mutated in a way that it can only serve as a catalytically inactive activator of kinases in the context of ErbB receptor heterodimers [9
]. Owing to their significant similarities, these receptors may form homo- as well as hetero-dimers, upon ligand binding, thus assembling a spectrum of activation options [10
]. To further increase this system’s complexity, ligands have evolved as well and are composed of a family of eleven molecules, distinct with respect to their expression patterns, binding specificities and affinities to the ErbB receptors [11
]. Remarkably, each ligand is unique in multiple aspects, which determine physiological roles, as well as oncogenicity. These include cleavage of the precursor form, retention in the extracellular environment, preference for certain receptor heterodimers and intracellular trafficking.
Despite multiple regulatory mechanisms acting at the levels of receptors and their downstream signaling pathways, which increase the robustness of this system, the ErbB family represents a major player in many types of malignancies. Robust as it is, every complex system has its weaknesses, and the ErbB system is not different: cellular transformation can arise from receptor gene amplification or overexpression, which is thought to promote dimerization by their shear numbers [17
], or, conversely, by self-production of ligands, which initiate signaling cascades in an autocrine manner [18
]. A third option of short-circuiting this highly regulated system is to bypass some of its inherent control. In this review, we will focus on the regulatory elements imposed by the molecular structure of EGFR, along with the question how cancer mutated its way to overcome these regulatory elements. In addition, we will highlight therapeutic approaches aiming to overcome aberrant modes of EGFR activation.