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

Kanakry CG, Li Z, Nakai Y, Sei Y, Weinberger DR - PLoS ONE (2007)

Bottom Line: Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis.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).

View Article: PubMed Central - PubMed

Affiliation: Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.

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 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.

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, 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).

Conclusion/significance: Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.

Show MeSH

Related in: MedlinePlus

Akt inhibition causes a dampening of the NRG/vehicle MRVA measure.Administration of the Akt Inhibitor X in water vehicle (n = 5) caused a dose-dependent decline in the NRG/vehicle MRVA (A). Unlike PI3K inhibition, Akt inhibition was associated with a statistically significant reduction in mean ICAM (B) and mean NRG (not shown) raw fluorescence values at the high dose only with no trend at lower doses. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2147048&req=5

pone-0001369-g005: Akt inhibition causes a dampening of the NRG/vehicle MRVA measure.Administration of the Akt Inhibitor X in water vehicle (n = 5) caused a dose-dependent decline in the NRG/vehicle MRVA (A). Unlike PI3K inhibition, Akt inhibition was associated with a statistically significant reduction in mean ICAM (B) and mean NRG (not shown) raw fluorescence values at the high dose only with no trend at lower doses. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.

Mentions: The Akt Inhibitor X selectively inhibits the phosphorylation of Akt with minimal effects on PI3K, PDK1, or SGK1 signaling. The effects of this drug mirrored the results of PI3K inhibition with a dose-dependent, significant reduction in NRG/vehicle MRVA (ANOVA, F(3,4) = 4.709, p = 0.0214) (Figure 5a) and no effects on ICAM-alone or PMA/vehicle MRVA. Unlike with PI3K inhibition, Akt inhibition was associated with a significant reduction in mean ICAM-alone attachment (ANOVA, F(3,4) = 6.711, p = 0.0086) (Figure 5b). However, this reduction was only seen at the highest dose (p = 0.0033). This same effect also was seen in significantly reducing the raw NRG fluorescence values at the high dose only (ANOVA, F(3,4) = 11.639, p = 0.0007) with no obvious trend at other doses. Given this common effect on mean ICAM-alone and mean NRG attachment exclusively at the high dose, it may represent a cross-reaction of the inhibitor at high concentrations with another signaling pathway important for maintaining an adhesive state.


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

Kanakry CG, Li Z, Nakai Y, Sei Y, Weinberger DR - PLoS ONE (2007)

Akt inhibition causes a dampening of the NRG/vehicle MRVA measure.Administration of the Akt Inhibitor X in water vehicle (n = 5) caused a dose-dependent decline in the NRG/vehicle MRVA (A). Unlike PI3K inhibition, Akt inhibition was associated with a statistically significant reduction in mean ICAM (B) and mean NRG (not shown) raw fluorescence values at the high dose only with no trend at lower doses. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2147048&req=5

pone-0001369-g005: Akt inhibition causes a dampening of the NRG/vehicle MRVA measure.Administration of the Akt Inhibitor X in water vehicle (n = 5) caused a dose-dependent decline in the NRG/vehicle MRVA (A). Unlike PI3K inhibition, Akt inhibition was associated with a statistically significant reduction in mean ICAM (B) and mean NRG (not shown) raw fluorescence values at the high dose only with no trend at lower doses. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.
Mentions: The Akt Inhibitor X selectively inhibits the phosphorylation of Akt with minimal effects on PI3K, PDK1, or SGK1 signaling. The effects of this drug mirrored the results of PI3K inhibition with a dose-dependent, significant reduction in NRG/vehicle MRVA (ANOVA, F(3,4) = 4.709, p = 0.0214) (Figure 5a) and no effects on ICAM-alone or PMA/vehicle MRVA. Unlike with PI3K inhibition, Akt inhibition was associated with a significant reduction in mean ICAM-alone attachment (ANOVA, F(3,4) = 6.711, p = 0.0086) (Figure 5b). However, this reduction was only seen at the highest dose (p = 0.0033). This same effect also was seen in significantly reducing the raw NRG fluorescence values at the high dose only (ANOVA, F(3,4) = 11.639, p = 0.0007) with no obvious trend at other doses. Given this common effect on mean ICAM-alone and mean NRG attachment exclusively at the high dose, it may represent a cross-reaction of the inhibitor at high concentrations with another signaling pathway important for maintaining an adhesive state.

Bottom Line: Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis.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).

View Article: PubMed Central - PubMed

Affiliation: Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.

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 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.

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, 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).

Conclusion/significance: Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.

Show MeSH
Related in: MedlinePlus