Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/akt-dependent pathway: Potential implications for schizoprenia and cancer

Abstract

Background. Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1α-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer. Methodology/Principal Findings. Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/ CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1α induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1α-induced migration (r2=0.61). NRG1α-induced adhesion variation is blocked by erbB2, P13K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/P13K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1α-induced adhesion (p=0.0002). In contrast, the response of patient derived cells to phorbol myristate acatate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1α-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p=0.063). Conclusion/Significance. Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.