Ral GTPases: Corrupting the exocyst in cancer cells

University of Texas at Dallas, Richardson, Texas, United States
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.
    Full-text · Article · Jan 2012 · Molecular biology of the cell
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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.
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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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