A role for PP1/NIPP1 in steering migration of human cancer cells

Cristina Martin-Granados, Alan R. Prescott, Nele Van Dessel, Aleyde Van Eynde, Miguel Arocena, Izabela P. Klaska, Janice Görnemann, Monique Beullens, Mathieu Bollen, John V. Forrester, Colin D. McCaig

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.
    Original languageEnglish
    Article numbere40769
    JournalPLoS ONE
    Volume7
    Issue number7
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    Phosphoric Monoester Hydrolases
    Cells
    cell lines
    electric field
    cell movement
    Neoplasms
    Cell Line
    Cell Movement
    cells
    phosphoprotein phosphatase
    Up-Regulation
    neoplasms
    uterine cervical neoplasms
    guanosinetriphosphatase
    prostatic neoplasms
    Holoenzymes
    Electric fields
    metastasis
    Phosphoprotein Phosphatases
    GTP Phosphohydrolases

    Keywords

    • Cell Line, Tumor
    • Cell Movement
    • Cell Polarity
    • Centrosome
    • Electricity
    • Electrodes
    • Endoribonucleases
    • Genes, Neoplasm
    • Humans
    • Models, Biological
    • Phosphoprotein Phosphatases
    • Protein Binding
    • Protein Phosphatase 1
    • RNA-Binding Proteins
    • Tetracycline
    • cdc42 GTP-Binding Protein

    Cite this

    Martin-Granados, C., Prescott, A. R., Van Dessel, N., Van Eynde, A., Arocena, M., Klaska, I. P., ... McCaig, C. D. (2012). A role for PP1/NIPP1 in steering migration of human cancer cells. PLoS ONE, 7(7), [e40769]. https://doi.org/10.1371/journal.pone.0040769
    Martin-Granados, Cristina ; Prescott, Alan R. ; Van Dessel, Nele ; Van Eynde, Aleyde ; Arocena, Miguel ; Klaska, Izabela P. ; Görnemann, Janice ; Beullens, Monique ; Bollen, Mathieu ; Forrester, John V. ; McCaig, Colin D. / A role for PP1/NIPP1 in steering migration of human cancer cells. In: PLoS ONE. 2012 ; Vol. 7, No. 7.
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    abstract = "Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.",
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    Martin-Granados, C, Prescott, AR, Van Dessel, N, Van Eynde, A, Arocena, M, Klaska, IP, Görnemann, J, Beullens, M, Bollen, M, Forrester, JV & McCaig, CD 2012, 'A role for PP1/NIPP1 in steering migration of human cancer cells', PLoS ONE, vol. 7, no. 7, e40769. https://doi.org/10.1371/journal.pone.0040769

    A role for PP1/NIPP1 in steering migration of human cancer cells. / Martin-Granados, Cristina; Prescott, Alan R.; Van Dessel, Nele ; Van Eynde, Aleyde; Arocena, Miguel; Klaska, Izabela P.; Görnemann, Janice; Beullens, Monique; Bollen, Mathieu; Forrester, John V.; McCaig, Colin D.

    In: PLoS ONE, Vol. 7, No. 7, e40769, 2012.

    Research output: Contribution to journalArticle

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    T1 - A role for PP1/NIPP1 in steering migration of human cancer cells

    AU - Martin-Granados, Cristina

    AU - Prescott, Alan R.

    AU - Van Dessel, Nele

    AU - Van Eynde, Aleyde

    AU - Arocena, Miguel

    AU - Klaska, Izabela P.

    AU - Görnemann, Janice

    AU - Beullens, Monique

    AU - Bollen, Mathieu

    AU - Forrester, John V.

    AU - McCaig, Colin D.

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    N2 - Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.

    AB - Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.

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    KW - Electrodes

    KW - Endoribonucleases

    KW - Genes, Neoplasm

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    KW - Models, Biological

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    Martin-Granados C, Prescott AR, Van Dessel N, Van Eynde A, Arocena M, Klaska IP et al. A role for PP1/NIPP1 in steering migration of human cancer cells. PLoS ONE. 2012;7(7). e40769. https://doi.org/10.1371/journal.pone.0040769