ZBP1 enhances cell polarity and reduces chemotaxis

Albert Einstein College of Medicine, New York, New York, United States
Journal of Cell Science (Impact Factor: 5.43). 10/2007; 120(Pt 18):3173-8. DOI: 10.1242/jcs.000638
Source: PubMed


The interaction of beta-actin mRNA with zipcode-binding protein 1 (ZBP1) is necessary for its localization to the lamellipod of fibroblasts and plays a crucial role in cell polarity and motility. Recently, we have shown that low ZBP1 levels correlate with tumor-cell invasion and metastasis. In order to establish a cause and effect relationship, we expressed ZBP1 in a metastatic rat mammary adenocarcinoma cell line (MTLn3) that has low endogenous ZBP1 levels and delocalized beta-actin mRNA. This leads to localization of beta-actin mRNA, and eventually reduces the chemotactic potential of the cells as well as their ability to move and orient towards vessels in tumors. To determine how ZBP1 leads to these two apparently contradictory aspects of cell behavior--increased cell motility but decreased chemotaxis--we examined cell motility in detail, both in cell culture and in vivo in tumors. We found that ZBP1 expression resulted in tumor cells with a stable polarized phenotype, and reduced their ability to move in response to a gradient in culture. To connect these results on cultured cells to the reduced metastatic ability of these cells, we used multiphoton imaging in vivo to examine tumor cell behavior in primary tumors. We found that ZBP1 expression actually reduced tumor cell motility and chemotaxis, presumably mediating their decreased metastatic potential by reducing their ability to respond to signals necessary for invasion.

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Available from: Kyle Lapidus, May 05, 2014
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    • "The localization of b-actin mRNAs to the leading edge of migrating cells and to neuronal growth cones of extending axons is associated with cell polarity, cell invasion and neuronal plasticity (Zhang et al., 1999; Condeelis and Singer, 2005; Lapidus et al., 2007). The localization process relies on a transacting RNA-binding protein, ZBP1 (also known as IGF2BP1), which contains a unique combination of two RNA recognition motifs (RRMs) and four hnRNP K homology (KH) domains, and specifically recognizes a cis-acting 'zipcode' within the 39 untranslated region (UTR) of b-actin mRNA (Ross et al., 1997; Farina et al., 2003; Hüttelmaier et al., 2005; Chao et al., 2010). "
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    ABSTRACT: ZBP1-modulated localization of β-actin mRNA enables a cell to establish polarity and structural asymmetry. While the mechanism of β-actin mRNA localization has been well revealed, the underlying mechanism of how a specific molecular motor contributes to transport of the ZBP1 complex in non-neuronal cells remains elusive. In this study, we report the isolation and identification of KIF11, a microtubule motor, which physically interacts with ZBP1 and is a component of β-actin mRNP. We show that KIF11 co-localizes with the β-actin mRNA and the ability of KIF11 to transport β-actin mRNA is ZBP1-dependent. We characterize the corresponding regions of ZBP1 and KIF11, which mediate the two protein's interaction in vitro and in vivo. Disruption of the in vivo interaction of KIF11 with ZBP1 delocalizes β-actin mRNA and affects cell migration. Our study reveals a molecular mechanism that a particular microtubule motor mediates the transport of an mRNP through the direct interaction with an mRNA-binding protein.
    Journal of Cell Science 01/2015; 128(5). DOI:10.1242/jcs.161679 · 5.43 Impact Factor
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    • "In agreement, we reported that IGF2BP1 promotes the directed migration of tumor cells derived from osteosarcoma, ovarian carcinoma as well as glioblastoma (25). This was also demonstrated in colorectal as well as mammary carcinoma-derived cells, in which IGF2BPs enhance the formation of lamellipodia and promote directed migration, respectively (26,27). Finally, IGF2BP1 and IGF2BP3 were suggested to enhance the invasive potential of cervical carcinoma-derived HeLa cells by interfering with the degradation of the CD44 mRNA (28). "
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    ABSTRACT: The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) controls the migration and invasiveness of primary as well as tumor-derived cells in vitro. Whether the protein also modulates epithelial-mesenchymal-transition (EMT), a hallmark of tumor progression involved in tumor cell dissemination, remained elusive. In this study, we reveal that IGF2BP1 enhances mesenchymal-like cell properties in tumor-derived cells by promoting the expression of the transcriptional regulators LEF1 and SLUG (SNAI2). IGF2BP1 associates with LEF1 transcripts and prevents their degradation in a 3'-UTR-dependent manner resulting in an upregulation of LEF1 expression. LEF1 promotes transcription of the mesenchymal marker fibronectin by associating with the fibronectin 1 promoter. Moreover, LEF1 enforces the synthesis of the 'EMT-driving' transcriptional regulator SNAI2. Accordingly, IGF2BP1 knockdown causes MET-like (mesenchymal-epithelial-transition) morphological changes, enhances the formation of cell-cell contacts and reduces cell migration in various mesenchymal-like tumor-derived cells. However, in epithelial-like tumor-derived cells characterized by a lack or low abundance of IGF2BP1, the protein fails to induce EMT. These findings identify IGF2BP1 as a pro-mesenchymal post-transcriptional determinant, which sustains the synthesis of 'EMT-driving' transcriptional regulators, mesenchymal markers and enhances tumor cell motility. This supports previous reports, suggesting a role of IGF2BP1 in tumor cell dissemination.
    Nucleic Acids Research 05/2013; 41(13). DOI:10.1093/nar/gkt410 · 9.11 Impact Factor
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    • "It is suggested that cells that are able to localize b-actin mRNA retain a stable and persistent polarity, leading to reduced responsiveness to orient towards exogenous chemotactic gradients; such responsiveness is required for cellular invasiveness and hence reduced metastatic potential (Lapidus et al., 2007). Interestingly, some in vivo studies reveal contradictory results for the role of ZBP1 in metastasis – a transgenic study indicated that targeted expression of ZBP1 in mouse breast induced tumorigenesis, and the levels of ZBP1 expression positively correlated with metastasis (Tessier et al., 2004); however, xenograft studies found that re-expression of ZBP1 in ZBP1-negative metastatic MTLn3 line reduces the metastatic potential of cell-derived breast tumors (Lapidus et al., 2007; Wang et al., 2004). Recent studies demonstrate that expression of the ZBP1 gene in mammalian cancer cells is a cellular response to Wnt/b-catenin signaling, which is frequently active in embryogenesis and tumorigenesis (Gu et al., 2009; Noubissi et al., 2006). "
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    ABSTRACT: Metastasis involves tumor cell detachment from the primary tumor, and acquisition of migratory and invasive capabilities. These capabilities are mediated by multiple events, including loss of cell-cell contact, an increase in focal adhesion turnover and failure to maintain a normal cell polarity. We have previously reported that silencing of the expression of the zipcode-binding protein IMP1/ZBP1 in breast tumor patients is associated with metastasis. IMP1/ZBP1 selectively binds to a group of mRNAs that encode important mediators for cell adhesion and motility. Here, we show that in both T47D and MDA231 human breast carcinoma cells IMP1/ZBP1 functions to suppress cell invasion. Binding of ZBP1 to the mRNAs encoding E-cadherin, β-actin, α-actinin and the Arp2/3 complex facilitates localization of the mRNAs, which stabilizes cell-cell connections and focal adhesions. Our studies suggest a novel mechanism through which IMP1/ZBP1 simultaneously regulates the local expression of many cell-motility-related mRNAs to maintain cell adherence and polarity, decrease focal adhesion turnover and maintain a persistent and directional motility.
    Journal of Cell Science 01/2012; 125(Pt 1):81-91. DOI:10.1242/jcs.086132 · 5.43 Impact Factor
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