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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.

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Related in: MedlinePlus

Phospholipase C (PLC) is essential for maintaining an adhesive state in general.While the PLC inhibitor U73122 in ethanol vehicle (n = 5) did cause a significant reduction in NRG/vehicle MRVA (A) and a trend towards reduction in PMA/vehicle MRVA (not shown), it exerted a much stronger effect on dampening baseline MRVA due to the presence of ICAM and endogeneous signaling alone (B). Furthermore, at high dose, it caused a significant reduction in baseline ICAM attachment (C) and in mean NRG and PMA attachment (raw fluorescence values) (not shown). However, mean NRG/vehicle (D) and mean PMA/vehicle (E) were not significantly changed. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, ++ represents p<0.01 and +++ represents p<0.001.
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pone-0001369-g006: Phospholipase C (PLC) is essential for maintaining an adhesive state in general.While the PLC inhibitor U73122 in ethanol vehicle (n = 5) did cause a significant reduction in NRG/vehicle MRVA (A) and a trend towards reduction in PMA/vehicle MRVA (not shown), it exerted a much stronger effect on dampening baseline MRVA due to the presence of ICAM and endogeneous signaling alone (B). Furthermore, at high dose, it caused a significant reduction in baseline ICAM attachment (C) and in mean NRG and PMA attachment (raw fluorescence values) (not shown). However, mean NRG/vehicle (D) and mean PMA/vehicle (E) were not significantly changed. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, ++ represents p<0.01 and +++ represents p<0.001.

Mentions: Like PI3K, the PLC inhibitor U73122 also caused a significant reduction in the NRG1α-induced MRVA (ANOVA, F(3,4) = 4.186, p = 0.0304) (Figure 6a), but the effect of this inhibitor seemed to be an overall reduction in cell attachment in general, and not an NRG1/erbB2-dependent effect. Both baseline variability (ICAM-alone MRVA) (ANOVA, F(3,4) = 8.883, p = 0.0023) and baseline mean attachment (mean ICAM-alone) (ANOVA, F(3,4) = 4.915, p = 0.0186) decreased after exposure to U73122 (Figures 6b and c, respectively). However, the change in mean ICAM-alone was only significant at the highest dose (p = 0.0155) (Figure 6c). Likewise, the raw mean NRG and PMA fluorescence values had significant decreases only at the highest dose (NRG: ANOVA, F(3,4) = 8.672, p = 0.0025; PMA: ANOVA, F(3,4) = 4.736, p = 0.0210). It is important to note, however, that neither the mean NRG/vehicle (Figure 6d) nor the mean PMA/vehicle (Figure 6e) ratios were significantly different across doses, indicating that PLC inhibition is affecting common cellular signaling across these pathways to a similar degree independent of the stimulatory agent. Therefore, although the PLC inhibitor did exert a significant effect on reducing the NRG/vehicle MRVA, this likely was due to reducing overall adhesion and constricting the range of the potential response, rather than to specific inhibition of an NRG1/erbB2-dependent pathway.


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)

Phospholipase C (PLC) is essential for maintaining an adhesive state in general.While the PLC inhibitor U73122 in ethanol vehicle (n = 5) did cause a significant reduction in NRG/vehicle MRVA (A) and a trend towards reduction in PMA/vehicle MRVA (not shown), it exerted a much stronger effect on dampening baseline MRVA due to the presence of ICAM and endogeneous signaling alone (B). Furthermore, at high dose, it caused a significant reduction in baseline ICAM attachment (C) and in mean NRG and PMA attachment (raw fluorescence values) (not shown). However, mean NRG/vehicle (D) and mean PMA/vehicle (E) were not significantly changed. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, ++ represents p<0.01 and +++ represents p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2147048&req=5

pone-0001369-g006: Phospholipase C (PLC) is essential for maintaining an adhesive state in general.While the PLC inhibitor U73122 in ethanol vehicle (n = 5) did cause a significant reduction in NRG/vehicle MRVA (A) and a trend towards reduction in PMA/vehicle MRVA (not shown), it exerted a much stronger effect on dampening baseline MRVA due to the presence of ICAM and endogeneous signaling alone (B). Furthermore, at high dose, it caused a significant reduction in baseline ICAM attachment (C) and in mean NRG and PMA attachment (raw fluorescence values) (not shown). However, mean NRG/vehicle (D) and mean PMA/vehicle (E) were not significantly changed. Compared with the vehicle control, * represents p<0.05 and ** represents p<0.01. Compared with the low dose, ++ represents p<0.01 and +++ represents p<0.001.
Mentions: Like PI3K, the PLC inhibitor U73122 also caused a significant reduction in the NRG1α-induced MRVA (ANOVA, F(3,4) = 4.186, p = 0.0304) (Figure 6a), but the effect of this inhibitor seemed to be an overall reduction in cell attachment in general, and not an NRG1/erbB2-dependent effect. Both baseline variability (ICAM-alone MRVA) (ANOVA, F(3,4) = 8.883, p = 0.0023) and baseline mean attachment (mean ICAM-alone) (ANOVA, F(3,4) = 4.915, p = 0.0186) decreased after exposure to U73122 (Figures 6b and c, respectively). However, the change in mean ICAM-alone was only significant at the highest dose (p = 0.0155) (Figure 6c). Likewise, the raw mean NRG and PMA fluorescence values had significant decreases only at the highest dose (NRG: ANOVA, F(3,4) = 8.672, p = 0.0025; PMA: ANOVA, F(3,4) = 4.736, p = 0.0210). It is important to note, however, that neither the mean NRG/vehicle (Figure 6d) nor the mean PMA/vehicle (Figure 6e) ratios were significantly different across doses, indicating that PLC inhibition is affecting common cellular signaling across these pathways to a similar degree independent of the stimulatory agent. Therefore, although the PLC inhibitor did exert a significant effect on reducing the NRG/vehicle MRVA, this likely was due to reducing overall adhesion and constricting the range of the potential response, rather than to specific inhibition of an NRG1/erbB2-dependent pathway.

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