Neuropathologic Implication of Peripheral Neuregulin-1 and EGF Signals in Dopaminergic Dysfunction and Behavioral Deficits Relevant to Schizophrenia: Their Target Cells and Time Window

Figure 7

Ectodomain shedding of EGF-like precursors and transactivation of ErbB receptors. Cytokines (yellow box) and GPCR ligands (green box) activate metalloproteases in a disintegrin and metalloprotease (ADAM) family (blue box) via the activation of protein kinase C (PKC). These metalloproteases cleave the precursor proteins for EGF-like factors in the cell membrane and liberates the core EGF domain (red box). The soluble EGF-like factor diffuses into blood stream and acts on ErbB receptors. Alternatively, cytokine-triggered NADPH oxidase (NOX) activation results in the production of reactive oxygen species (ROS) and hydrogen peroxide, which inhibits the protein phosphatases (i.e., SHP2 or PTP1B) for ErbB kinases. UV or gamma ray irradiation (purple box) directly produces ROS and hydrogen peroxide. The attenuation of the phosphatases SHP2 (Src homology 2-containing protein tyrosine phosphatase) or PTP1B (protein tyrosine phosphatase 1B) markedly elevates basal phosphorylation (P) levels of ErbB receptors.