The EGF receptor family: spearheading a merger of signaling and therapeutics

The ErbB receptor tyrosine kinases evolved as key regulatory entities enabling the extracellular milieu to communicate with the intracellular machinery to bring forth the appropriate biological response in an ever-changing environment. Since its discovery, many aspects of the ErbB family have been deciphered, with emphasis on aberration of signaling in human diseases. However, only now, with the availability of the atomic coordinates of these receptors, can we construct a comprehensive model of the mechanisms underlying ligand-induced receptor dimerization and subsequent tyrosine kinase activation. Furthermore, the recent introduction of new high-throughput screening methodologies, combined with the materialization of a systems biology perspective, reveals an overwhelming network complexity, enabling robust signaling and evolvability. This knowledge is likely to impact our view of diseases as system perturbations and resistance to ErbB-targeted therapeutics as manifestations of robustness.

Introduction

When a growth factor acts upon a specific cell surface receptor harboring a tyrosine kinase activity, cell fate decisions are affected through a complex succession of signaling events. The large family of growth factor receptor tyrosine kinases (RTKs) may be considered as allosteric enzymes, whose regulatory portion binds the allosteric regulator, a ligand growth factor of relatively low molecular weight, and consequently undergoes large-scale conformational changes leading to receptor dimerization. As a result, the catalytic kinase portion, which faces the intracellular milieu, undergoes activation and transfers phosphate groups to the tyrosine residues of nearby molecules, including dimer partners and substrate proteins participating in signal transfer. Among all RTKs, the ErbB family (also called the type I RTKs) is considered the prototypic founder sub-group of the RTK super-family, which includes 18 other small sub-groups of related receptors.

Two out of the four ErbB proteins, namely ErbB-1 (also called epidermal growth factor receptor; EGFR) and ErbB-4, are autonomous; when bound by a ligand growth factor they undergo dimerization and generate intracellular signals culminating in cell proliferation, migration or differentiation. The other two receptors are non-autonomous: ErbB-2 (also called HER2 in human and Neu in rodents) binds no soluble ligand, but acts as a preferred partner in heterodimeric complexes with other, ligand-bound ErbBs. On the other hand, ErbB-3 cannot generate signals in isolation because the kinase function of this receptor is impaired. Nevertheless, in the context of a heterodimer, primarily with ErbB-2, ErbB-3 can mount potent intracellular signals. Interestingly, ErbB-1, -3 and -4 can each bind several distinct ligand molecules, which, according to genetic evidence, are partially redundant in their function.

This review concentrates on recent advances in understanding the mechanism of allosteric activation of ErbB proteins, as well as attempts to achieve a global view of ErbB signaling using computational modeling and high-throughput strategies. ErbB translocation from the plasma membrane, an area of intense investigation, is presented in Figure 1. Because ErbB proteins and their ligands are richly involved in human pathologies, and they already serve as targets for cancer therapeutics, we describe the current implications of ErbB signaling in diseases. The reader is directed to several recent reviews covering a system level approach to ErbB signaling [1] and its roles in human pathology [2], including cancer [3].