Ral GTPases: Corrupting the exocyst in cancer cells

Institut Curie, INSERM U-528, Paris, France.
Trends in Cell Biology (Impact Factor: 12.01). 07/2005; 15(6):327-32. DOI: 10.1016/j.tcb.2005.04.002
Source: PubMed


The Ras-like small G-proteins RalA and RalB have achieved some notoriety as components of one of a growing variety of candidate Ras effector pathways. Recent work has demonstrated that Ral GTPase activation is required to support both the initiation and maintenance of tumorigenic transformation of human cells. The mechanistic basis for this support remains to be defined. However, the discovery that the exocyst is a direct effector complex for activated Ral proteins suggests that mobilization of polarized exocytosis might be a basic component of the biological framework supporting tumorigenic progression.

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    • "A migratory cell requires de novo plasma membrane addition at the leading edge that is driven by membrane traffic (Lim et al., 2005). This occurs through use of the small-GTPase RalB to confine vesicle trafficking to the leading edge, achieving directional cell movement (Camonis and White, 2005; Rosse et al., 2006). These vesicles then tether at the leading edge via the RalB-recruited-exocyst complex (Rosse et al., 2006), suggesting that localized membrane addition is required to create a polarized migrating cell. "
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    ABSTRACT: Cell polarity is important for a number of processes, from chemotaxis to embryogenesis. Recent studies suggest a new role for polarity in the orchestration of events during the final cell separation step of cell division called abscission. Abscission shares several features with cell polarization, including rearrangement of phosphatidylinositols, reorganization of microtubules, and trafficking of exocyst-associated membranes. Here we focus on how the canonical pathways for cell polarization and cell migration may play a role in spatiotemporal membrane trafficking events required for the final stages of cytokinesis.
    Molecular biology of the cell 01/2012; 23(1):7-11. DOI:10.1091/mbc.E11-06-0512 · 4.47 Impact Factor
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    • "These results are consistent with the idea that RalA and RalB contribute to different aspects of tumorigenesis. Earlier, it was suggested that RalA was essential for anchorage-independent growth of transformed cells while RalB was responsible for tumor cell-autonomous survival [6,14,19,20]. Data published later proposed the mechanisms of RalB anti-apoptotic action through activation of RalB/TBK1 signaling pathway [38,39]. Moreover, Lim et al. showed that RalA knockdown reduced tumorigenic growth of transformed cells (pancreatic cancer cell lines) while RalB inhibition decreased invasion and experimental metastasis [15]. "
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    ABSTRACT: Previously we have shown that oncogenic Ha-Ras stimulated in vivo metastasis through RalGEF-Ral signaling. RalA and RalB are highly homologous small G proteins belonging to Ras superfamily. They can be activated by Ras-RalGEF signaling pathway and influence cellular growth and survival, motility, vesicular transport and tumor progression in humans and in animal models. Here we first time compared the influence of RalA and RalB on tumorigenic, invasive and metastatic properties of RSV transformed hamster fibroblasts. Retroviral vectors encoding activated forms or effector mutants of RalA or RalB proteins were introduced into the low metastatic HET-SR cell line. Tumor growth and spontaneous metastatic activity (SMA) were evaluated on immunocompetent hamsters after subcutaneous injection of cells. The biological properties of cells, including proliferation, clonogenicity, migration and invasion were determined using MTT, wound healing, colony formation and Boyden chamber assays respectively. Protein expression and phosphorylation was detected by Westen blot analysis. Extracellular proteinases activity was assessed by substrate-specific zymography. We have showed that although both Ral proteins stimulated SMA, RalB was more effective in metastasis stimulation in vivo as well as in potentiating of directed movement and invasion in vitro. Simultaneous expression of active RalA and RalB didn't give synergetic effect on metastasis formation. RalB activity decreased expression of Caveolin-1, while active RalA stimulated MMP-1 and uPA proteolytic activity, as well as CD24 expression. Both Ral proteins were capable of Cyclin D1 upregulation, JNK1 kinase activation, and stimulation of colony growth and motility. Among three main RalB effectors (RalBP1, exocyst complex and PLD1), PLD1 was essential for RalB-dependent metastasis stimulation. Presented results are the first data on direct comparison of RalA and RalB impact as well as of RalA/RalB simultaneous expression influence on in vivo cell metastatic activity. We showed that RalB activation significantly more than RalA stimulates SMA. This property correlates with the ability of RalB to stimulate in vitro invasion and serum directed cell movement. We also found that RalB-PLD1 interaction is necessary for the acquisition of RalB-dependent high metastatic cell phenotype. These findings contribute to the identification of molecular mechanisms of metastasis and tumor progression.
    Cancer Cell International 06/2011; 11(1):22. DOI:10.1186/1475-2867-11-22 · 2.77 Impact Factor
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    • "For many years, it was assumed that Ral GTPases merely facilitated the cascade of Ras GTPase signaling events. Recent studies have determined that the effectors of Ral GTPases have been implicated in vesicle transport (Camonis and White, 2005; Rosse et al., 2006), endocytosis (Jullien-Flores et al., 2000), gene transcription (Frankel et al., 2005), development of filopodia (Ohta et al., 1999) and cellular proliferation (Smith et al., 2006). In addition to these effectors, recent research has determined that improper activation of Ral GTPases has been implicated in oncogenesis through its role in metastasis (Lim et al., 2005; Lim et al., 2006; Oxford and Theodorescu, 2003), resistance to anoikis (Zahir et al., 2003), activation of transcription factors (Frankel et al., 2005) and inappropriate cell survival signals (Chien et al., 2006; Smith et al., 2006). "
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    ABSTRACT: The Ras superfamily of GTPases is involved in the modification of many cellular processes including cellular motility, proliferation and differentiation. Our laboratory has previously identified the RalGDS-related (Rgr) oncogene in a DMBA (7,12-dimethylbenz[α]anthracene)-induced rabbit squamous cell carcinoma and its human orthologue, hRgr. In this study, we analyzed the expression levels of the human hRgr transcript in a panel of human hematopoietic malignancies and found that a truncated form (diseased-truncated (Dtr-hrgr)) was significantly overexpressed in many T-cell-derived neoplasms. Although the Rgr proto-oncogene belongs to the RalGDS family of guanine nucleotide exchange factors (GEFs), we show that upon the introduction of hRgr into fibroblast cell lines, it is able to elicit the activation of both Ral and Ras GTPases. Moreover, in vitro guanine nucleotide exchange assays confirm that hRgr promotes Ral and Ras activation through GDP dissociation, which is a critical characteristic of GEF proteins. hRgr has guanine nucleotide exchange activity for both small GTPases and this activity was reduced when a point mutation within the catalytic domain (CDC25) of the protein, (cd) Dtr-hRgr, was utilized. These observations prompted the analysis of the biological effects of hRgr and (cd) hRgr expression in cultured cells. Here, we show that hRgr increases proliferation in low serum, increases invasion, reduces anchorage dependence and promotes the progression into the S phase of the cell cycle; properties that are abolished or severely reduced in the presence of the catalytic dead mutant. We conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T-cell malignancies.
    Oncogene 03/2011; 30(34):3661-71. DOI:10.1038/onc.2011.93 · 8.46 Impact Factor
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