Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members

Abstract

ErbB (also termed HER) receptors are expressed in various tissues of epithelial, mesenchymal and neuronal origin, in which they are involved in the control of diverse biological processes such as proliferation, differentiation, migration and apoptosis. Furthermore, their deregulated expression has been implicated in many types of human cancers and is associated with poor clinical prognosis. Owing to the importance of ErbB proteins in both development and cellular transformation, a lot of attention has been drawn to the intracellular signals initiated by the engagement of this family of receptor tyrosine kinases. This review will focus on the membrane proximal events triggered by the ErbB receptor network and will address questions of how receptor heterodimerization may contribute to signal specification and diversification.

Figure 1

ErbB receptors and their cytoplasmic partners. The interaction of various proteins containing Src homology 2 and phosphotyrosine binding domains has been mapped to specific ErbB carboxy-terminal tyrosines. Autophosphorylation sites are shown in red, interaction sites demonstrated by phosphopeptide competition analyses are in black, and sites identified as Src phosphorylation sites are in blue. The receptor-associated late transducer (Ralt) and the PDZ proteins PSD-95, Erbin and Pick1 interact with the receptors in a phosphorylation-independent manner.

Figure 2

Heterodimerization modulates ErbB signaling. Ligand binding triggers ErbB dimerization and kinase activation, leading to phosphorylation of carboxy-terminal tyrosine residues in trans. When ErbB2 is expressed, mainly ErbB2-containing heterodimers are formed that, when compared with their homodimeric counterparts, possess altered signaling properties. EGF, epidermal growth factor; NRG, neuregulin; P, phosphotyrosine.