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

COMT Val108/158Met predicts variation in cell adhesion.COMT, a putative susceptibility gene for both schizophrenia and metastatic cancer, previously was shown to have genotype effects on cell migration with the risk genotype rs4680 V/V showing the most impaired migration. In our adhesion data (n = 40), there was a strong trend (p = 0.0632) towards decreased NRG1α-induced MRVA of risk homozygotes compared with non-risk homozygotes (no heterozygote cell lines are maintained).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2147048&req=5

pone-0001369-g009: COMT Val108/158Met predicts variation in cell adhesion.COMT, a putative susceptibility gene for both schizophrenia and metastatic cancer, previously was shown to have genotype effects on cell migration with the risk genotype rs4680 V/V showing the most impaired migration. In our adhesion data (n = 40), there was a strong trend (p = 0.0632) towards decreased NRG1α-induced MRVA of risk homozygotes compared with non-risk homozygotes (no heterozygote cell lines are maintained).

Mentions: Given the relationship of single nucleotide polymorphisms in COMT (val108/158met, rs4680) and in NRG1 (rs6994992) to NRG1α-induced cell migration established previously,[7] we sought to determine if NRG1α-induced cell adhesion also showed such associations. The presence of the schizophrenia risk-associated COMT val allele showed a strong trend towards predicting smaller NRG1α-induced MRVA in the entire sample with similar effects in both groups (unpaired t-test, p = 0.0632) (Figure 9a). ANOVA performed with diagnostic group and genotype as independent factors revealed no genotype by diagnosis interactions for either gene. Additionally, there was no effect of COMT genotype on PMA-induced MRVA (unpaired t-test, p = 0.8727). Because of the low minor allele frequency at NRG1 rs6994992, our study was underpowered to test for an association with this SNP.


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)

COMT Val108/158Met predicts variation in cell adhesion.COMT, a putative susceptibility gene for both schizophrenia and metastatic cancer, previously was shown to have genotype effects on cell migration with the risk genotype rs4680 V/V showing the most impaired migration. In our adhesion data (n = 40), there was a strong trend (p = 0.0632) towards decreased NRG1α-induced MRVA of risk homozygotes compared with non-risk homozygotes (no heterozygote cell lines are maintained).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001369-g009: COMT Val108/158Met predicts variation in cell adhesion.COMT, a putative susceptibility gene for both schizophrenia and metastatic cancer, previously was shown to have genotype effects on cell migration with the risk genotype rs4680 V/V showing the most impaired migration. In our adhesion data (n = 40), there was a strong trend (p = 0.0632) towards decreased NRG1α-induced MRVA of risk homozygotes compared with non-risk homozygotes (no heterozygote cell lines are maintained).
Mentions: Given the relationship of single nucleotide polymorphisms in COMT (val108/158met, rs4680) and in NRG1 (rs6994992) to NRG1α-induced cell migration established previously,[7] we sought to determine if NRG1α-induced cell adhesion also showed such associations. The presence of the schizophrenia risk-associated COMT val allele showed a strong trend towards predicting smaller NRG1α-induced MRVA in the entire sample with similar effects in both groups (unpaired t-test, p = 0.0632) (Figure 9a). ANOVA performed with diagnostic group and genotype as independent factors revealed no genotype by diagnosis interactions for either gene. Additionally, there was no effect of COMT genotype on PMA-induced MRVA (unpaired t-test, p = 0.8727). Because of the low minor allele frequency at NRG1 rs6994992, our study was underpowered to test for an association with this SNP.

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