Mechanisms of action of ErbB receptor. In tumor cells, ErbB receptor tyrosine kinases are activated by autocrine or paracrine production of EGF family ligands. Autocrine ligand production results from the activation of G-protein coupled receptors (GPCRs) or frizzled (FZD) receptor which causes the metalloproteinases-mediated cleavage and release of pro-EGF-related ligands (ectodomain shedding). Binding of ligands to the extracellular domain of ErbB receptors leads to receptor dimerization, autophosphorylation, and activation of several downstream signalling pathways. In particular, tyrosine-phosphorylated ErbB receptors bind the adaptor proteins Shc and Grb2 leading to Sos recruitment and Ras/MAPK pathway activation. The PI3K/Akt pathway is stimulated through recruitment of the p85 adaptor subunit of PI3K to the receptor.
