ERBB: The receptor network

ERBB receptors (also called HER receptors) are composed of an extra-cellular domain (comprising subdomains I–IV), a single transmembrane portion, and a large intra-cellular domain comprising a short juxtamembrane portion, a bilobular tyrosine kinase domain and a carboxyl-terminal tail. The principal ERBB receptor activation mechanism involves ligand binding, which activates the kinase domains of receptor homo- and heterodimers. Notably, the ligandless ERBB2 and the kinase-dead ERBB3 are non-autonomous, yet confer potent signaling upon heterodimerization. Activated kinase domains then phosphorylate tyrosine residues located in the cytoplasmic receptor's portion, which serve as docking sites for proteins containing phosphotyrosine-binding or Src homology-2 domains (Figure 10.1). These signaling effectors and adaptor proteins link activated receptors directly or indirectly to canonical intra-cellular pathways, depicted in Figure 10.2, as well as to the endocytic, desensitizing machinery. Although there is considerable overlap amongst the individual ERBB receptors with regards to the recruited signaling effectors and adaptor proteins, the stoichiometry of recruited adaptors varies, and some pathways are unique to individual receptors (1,2). Moreover, many tyrosine residues can bind several adaptors and effectors, which, in turn, can act as molecular scaffolds. For instance, phosphorylated tyrosine residues 1068 and 1086 of the EGFR recruit the adaptor protein Grb2, which can bind both positive (Sos) and negative (e.g. Cbl, Ship, Socs, Sprouty, Ack1) regulators of EGFR signaling. Further fine-tuning of receptor activity and connectivity is achieved by phosphorylation of cytoplasmic ERBB receptor residues by intra-cellular kinases (e.g. Src phosphorylates EGFR on multiple residues, including tyrosine 845, which then serves as a novel docking site for STAT5b (3)). ERBB signaling may both activate and undergo activation by several heterologous receptors (e.g. the HGF-receptor MET) through multiple mechanisms, including formation of signaling-competent receptor heteromers, receptor transmodulation, and by transcriptional induction of heterologous ligands and receptors.