RalB GTPase-Mediated Activation of the IκB Family Kinase TBK1 Couples Innate Immune Signaling to Tumor Cell Survival

Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Cell (Impact Factor: 32.24). 11/2006; 127(1):157-70. DOI: 10.1016/j.cell.2006.08.034
Source: PubMed


The monomeric RalGTPases, RalA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RalB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RalB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RalB/Sec5 effector complex directly recruits and activates the atypical IkappaB kinase family member TBK1. In cancer cells, constitutive engagement of this pathway, via chronic RalB activation, restricts initiation of apoptotic programs typically engaged in the context of oncogenic stress. Although dispensable for survival in a nontumorigenic context, this pathway helps mount an innate immune response to virus exposure. These observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.

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    • "RalB has been shown to be involved in many important biological processes such as the host immune response (Chien et al., 2006), tumorigenesis (Peschard et al., 2012), tumor cell invasion and metastasis (Bodemann and White, 2008; Neel et al., 2012), control of autophagy (Bodemann et al., 2011), and exocytosis (Martin et al., 2012). Despite controlling diverse biological functions , RalB is only known to interact with a limited number of effector proteins (Martin and Der, 2012). "
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    • "It has been reported that viruses can activate various host signaling pathways mediated by some small GTPases to modulate microtubule-based transport of virus particles from the plasma membrane to the nucleus during the establishment of infection [28], [29]. TCTP is thought to be a modulator of GTPase activity, acting as a molecular switch for a vast number of cellular processes in all eukaryotes [30]. "
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    • "Accumulating evidence demonstrates that TBK1 and IKKE play important roles in tumorigenesis and survival [6] [9] [10] [24] [25] and are expressed by tumor cells under stressful growth conditions [8] including those that predominate in the HSC niche [26] [27] [28]. To evaluate whether the binding of PCa cells to niche osteoblasts induces the expression of TBK1 and IKKE in PCa cells, PCa cells were co-cultured with ST2 cells and then analyzed by qPCR. "
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