Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer.
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 NRG1alpha-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.


RESULTS
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, NRG1alpha 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 NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/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 NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063).


CONCLUSIONS
Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.
Kanakry
Christopher G
CG
Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.
Li
Zhen
Z
Nakai
Yoko
Y
Sei
Yoshitatsu
Y
Weinberger
Daniel R
DR
D002448:Cell Adhesion / Q000502:physiology*; D006801:Humans; D018716:Molecular Mimicry; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D020890:Neuregulin-1 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D012559:Schizophrenia / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D010738:Type C Phospholipases