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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

Neuregulin-1 induces temporally varying cell adhesion that appears characteristic of a particular cell line.In response to NRG1α stimulation over time, cells of a given cell line as a population fluctuate between states of relative detachment and states of relative attachment. In order to test the reliability of these patterns, ten cell lines on two separate days were tested using our adhesion assay. Two representative examples are shown. While the timing of peaks and troughs varied between runs, the maximum range of varying adhesion (MRVA) was remarkably consistent (p = 0.016). Calculation of the MRVA for each run of each cell line is shown.
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pone-0001369-g001: Neuregulin-1 induces temporally varying cell adhesion that appears characteristic of a particular cell line.In response to NRG1α stimulation over time, cells of a given cell line as a population fluctuate between states of relative detachment and states of relative attachment. In order to test the reliability of these patterns, ten cell lines on two separate days were tested using our adhesion assay. Two representative examples are shown. While the timing of peaks and troughs varied between runs, the maximum range of varying adhesion (MRVA) was remarkably consistent (p = 0.016). Calculation of the MRVA for each run of each cell line is shown.

Mentions: Initial experiments with our adhesion assay suggested that adhesion had a time dependency. So, time course experiments were performed in which lymphoblasts were exposed to NRG1α or phorbol myristate acetate (PMA) in ICAM-coated plates for either 15, 30, 45, or 60 minutes, and then the plates were washed to remove cells that were not firmly adherent. PMA was used as a positive control as it promotes cell attachment by directly activating PKC. For each cell line, cells were subjected for the same time exposure to the ICAM-coated plates in the absence of NRG1α or PMA. Variation in the raw NRG1 attachment data (Figure S1) and in the NRG/vehicle ratio over time (Figure 1, Figure S1, Figure S2, and Figure S3) indicated that NRG1α-stimulated cells as a population were fluctuating between states of relatively firmer and weaker attachment compared with baseline control adhesion. In order to quantify the observed variation in cell adhesion, we defined the NRG1-induced maximum range of varying adhesion (MRVA) as the maximum NRG/vehicle ratio minus the minimum NRG/vehicle ratio of the four time points (Figure 1).


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)

Neuregulin-1 induces temporally varying cell adhesion that appears characteristic of a particular cell line.In response to NRG1α stimulation over time, cells of a given cell line as a population fluctuate between states of relative detachment and states of relative attachment. In order to test the reliability of these patterns, ten cell lines on two separate days were tested using our adhesion assay. Two representative examples are shown. While the timing of peaks and troughs varied between runs, the maximum range of varying adhesion (MRVA) was remarkably consistent (p = 0.016). Calculation of the MRVA for each run of each cell line is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001369-g001: Neuregulin-1 induces temporally varying cell adhesion that appears characteristic of a particular cell line.In response to NRG1α stimulation over time, cells of a given cell line as a population fluctuate between states of relative detachment and states of relative attachment. In order to test the reliability of these patterns, ten cell lines on two separate days were tested using our adhesion assay. Two representative examples are shown. While the timing of peaks and troughs varied between runs, the maximum range of varying adhesion (MRVA) was remarkably consistent (p = 0.016). Calculation of the MRVA for each run of each cell line is shown.
Mentions: Initial experiments with our adhesion assay suggested that adhesion had a time dependency. So, time course experiments were performed in which lymphoblasts were exposed to NRG1α or phorbol myristate acetate (PMA) in ICAM-coated plates for either 15, 30, 45, or 60 minutes, and then the plates were washed to remove cells that were not firmly adherent. PMA was used as a positive control as it promotes cell attachment by directly activating PKC. For each cell line, cells were subjected for the same time exposure to the ICAM-coated plates in the absence of NRG1α or PMA. Variation in the raw NRG1 attachment data (Figure S1) and in the NRG/vehicle ratio over time (Figure 1, Figure S1, Figure S2, and Figure S3) indicated that NRG1α-stimulated cells as a population were fluctuating between states of relatively firmer and weaker attachment compared with baseline control adhesion. In order to quantify the observed variation in cell adhesion, we defined the NRG1-induced maximum range of varying adhesion (MRVA) as the maximum NRG/vehicle ratio minus the minimum NRG/vehicle ratio of the four time points (Figure 1).

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