ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease

Abstract

Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson's disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes, and their precursors. Thus, deficits in ErbB signaling might contribute to the neurological and psychiatric diseases stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and neuregulin-1 in brain diseases are also discussed.

Keywords: ErbB1-4; GABA; Parkinson's disease; dopamine; schizophrenia; virokine.

Figure 1

ErbB receptor dimerization and activation. The ligand interaction with ErbB 1, 3, and 4 increases their affinity and induces homo- or heterodimerization of ErbB1-4. This dimerization activates the tyrosine kinase domain and allows it to phosphorylate the cytoplasmic region of the ErbB partner. The phosphorylated tyrosine residues recruit various adaptors/effectors that induce intracellular signals.

Figure 2

ErbB receptors and their ligands. The molecular structure of ErbB receptors and proteolytic processing of their ligands are displayed.

Figure 3

Typical signal transduction from the ErbB4:ErbB1 and ErbB4:ErbB4 complex. Once ErbB1 is phosphorylated by the partner ErbB, the following signal cascades are activated; (1) In the PLCγ-PKC pathway, phosphorylated ErbB1 recruits and associates with PLCγ. As a result, PLCγ itself is phosphorylated to activate DAG/IP3 signaling (Chen et al., 1996). (2) In the Ras-MAPK pathway, phosphorylated ErbB1 associates with Shc and interacts with Grb2/Sos1. Activated Sos1 triggers GDP/GTP exchange in Ras and activates Ras, driving the sequential kinase reactions of Raf(MAPKKK), MEK(MAPKK), and Erk(MAPK). (3) In the PI3K-Akt pathway, the activated ErbB dimer interacts with Grb2/Gab1 and forms complexes with activated PI3Kinase, leading to the conversion of PIP2 to PIP3 and Akt activation. (4) In the JAK-STAT pathway, ErbB kinase phosphorylates and induces JAK to bind to ErbB1. Activated JAK phosphorylates STAT and allows STAT to homodimerize and translocate into the nucleus. Once ErbB4 is phosphorylated by ErbB4, the signaling cascades linked to differentiation become activated, notably the PI3K-Akt pathway and the Ras-MAPK pathway with longer durations.

Figure 4

Splice variants of ErbB4 proteins and their specific signaling. The JM-a and JM-d isoforms of ErbB4 are cleaved by TACE or γ-secretase and converted to ErbB4-ICD. ErbB4-ICD is translocated into the nucleus with STAT and regulates gene transcription (A). The CYT-1 and CYT-2 isoforms of ErbB4 differentially trigger Ras-MAPK signaling and/or PI3K-Akt signaling (B).

Figure 5

Synaptic compartment of ErbB4 that binds to PSD95 or interacts with the phosphatase. The scaffolding protein PSD95 anchors ErbB4 and the NMDA receptor at postsynaptic sites. The molecular interaction between ErbB4 influences NMDA receptor activity and function (A). The PSD95-mediated interaction between ErbB4 and a membrane attached phosphatase, Ptprz. Ptprz eliminates the phosphate from ErbB4 and attenuates its signaling (B).

Figure 6

Primary sequences of ErbB-interacting virokines and receptor interactions. The primary amino acid sequences of EGF and virokines in the poxvirus family are shown (A). An ErbB adaptor, E5, which is produced by papillomaviruses, associates with the kinase domain of ErbB and inhibits its internalization and/or degradation (B).