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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

The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin is essential for variation in NRG1α-induced cell adhesion.Wortmannin in DMSO vehicle (n = 5) exhibited a strong, dose-dependent, dampening effect on the NRG/vehicle MRVA measure. Compared with the vehicle control, * represents p<0.05, ** represents p<0.01, and **** represents p<0.0001. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.
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pone-0001369-g004: The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin is essential for variation in NRG1α-induced cell adhesion.Wortmannin in DMSO vehicle (n = 5) exhibited a strong, dose-dependent, dampening effect on the NRG/vehicle MRVA measure. Compared with the vehicle control, * represents p<0.05, ** represents p<0.01, and **** represents p<0.0001. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.

Mentions: To address the role of PI3K signaling in the NRG1α-induced adhesion effect, we studied the irreversible PI3K inhibitor wortmannin. The doses used were all well below concentrations in which wortmannin cross-reacts with MAPK, myosin light chain kinase (MLCK), or phosphoinositide-4 kinase signaling in an effort to specifically target PI3K signaling. Wortmannin exhibited a significant, dose-dependent, dampening effect on the NRG/vehicle MRVA (ANOVA, F(3,4) = 17.208, p<0.0001) (Figure 4) with no effects on baseline or PMA-induced adhesion.


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)

The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin is essential for variation in NRG1α-induced cell adhesion.Wortmannin in DMSO vehicle (n = 5) exhibited a strong, dose-dependent, dampening effect on the NRG/vehicle MRVA measure. Compared with the vehicle control, * represents p<0.05, ** represents p<0.01, and **** represents p<0.0001. 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-g004: The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin is essential for variation in NRG1α-induced cell adhesion.Wortmannin in DMSO vehicle (n = 5) exhibited a strong, dose-dependent, dampening effect on the NRG/vehicle MRVA measure. Compared with the vehicle control, * represents p<0.05, ** represents p<0.01, and **** represents p<0.0001. Compared with the low dose, + represents p<0.05 and ++ represents p<0.01.
Mentions: To address the role of PI3K signaling in the NRG1α-induced adhesion effect, we studied the irreversible PI3K inhibitor wortmannin. The doses used were all well below concentrations in which wortmannin cross-reacts with MAPK, myosin light chain kinase (MLCK), or phosphoinositide-4 kinase signaling in an effort to specifically target PI3K signaling. Wortmannin exhibited a significant, dose-dependent, dampening effect on the NRG/vehicle MRVA (ANOVA, F(3,4) = 17.208, p<0.0001) (Figure 4) with no effects on baseline or PMA-induced adhesion.

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