Untangling the ErbB signalling network

Abstract

The four ErbB receptors and their many neuregulins and EGF-like ligands form a layered signalling network. The network structure allows the diversification, tuning and robustness of cell-to-cell signalling. The network evolved from a simple signalling module that controls inductive morphogenesis in invertebrates. In mammals, specific ligands and their respective homo- or heterodimeric ErbB complexes specify different cell lineages. Oncogenic animal viruses harness the network through diverse molecular processes that promote ErbB signalling or prevent it from being switched off. Autocrine loops, mutant ErbB1 molecules and enhanced expression of ErbB receptors are frequently observed in human cancers of epithelial and neuronal origins. Most frequent is overexpression of ErbB2, a ligandless co-receptor that amplifies ErbB signalling. Current attempts to block the network in human disease include small-molecule inhibitors of tyrosine kinases and chaperones, and various gene-therapy strategies. But immunotherapy directed at ErbB2 is already widely used, in combination with chemotherapy, to inhibit metastasizing breast cancers. Future pharmacological advances and deeper understanding of the network will allow selective inhibition or activation of its many routes, with the aim of curing neuronal and skin disorders, as well as cancer.