Key Points
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Chronic activation of the Ras-like (Ral) guanyl nucleotide-binding proteins, RALA and RALB, occurs in tumour-derived cell lines and tumour samples.
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Depletion of RALA severely impairs the anchorage-independent proliferation of cancer cell lines, whereas RALB seems to be essential for the survival of a variety of tumour-derived cell lines.
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RALA is phosphorylated by Aurora kinase A and other, yet to be identified kinases. It is also a substrate of protein phosphatase 2A Aβ. Evidence indicates that dephosphorylation of RALA is a major mechanism by which PP2A Aβ normally restricts tumour progression.
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The effects on tumorigenesis of well-characterised downstream effectors of Ral, such as the Rac-family GTPase-activating protein RLIP, the Y-box transcription factor ZO-1-associated nucleic acid-binding protein (ZONAB) and two subunits of the exocyst complex, SEC5 and EXO84, remain unclear. However, a number of relationships have been identified that might explain Ral-dependent modulation of cell proliferation and survival.
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An important factor that might explain the occurrence of Ral activation in tumorigenesis is the RALB-specific contribution to cancer cell survival through activation of TANK-binding kinase 1 (TBK1). Chronic RALB activation restricts initiation of apoptotic programmes that are normally activated in the context of oncogenic stress.
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Proteins such as TBK1 might prove to be good candidate targets for the development of cancer drugs with a large therapeutic window.
Abstract
A confluence of recent observations has indicted the Ras-family G-proteins RALA and RALB as key offenders in the subversion of core biological systems driving oncogenic transformation. Here, we will focus on current developments highlighting the pivotal contribution of Ral proteins to the regulatory framework supporting tumorigenesis, and evaluate mechanistic connections between Ral effector activation and generation of this framework.
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Glossary
- Geranylgeranyltransferase 1
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(GGTase 1). One of the three enzymes in the prenyltransferase group. GGTase 1 adds a 20-carbon isoprenoid called a geranylgeranyl group to proteins bearing a CaaX motif (a four amino-acid sequence at the C terminus of a protein).
- Farnesylation
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After translation, the Ras proteins undergo four modification steps: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase, which transfers a farnesyl group from farnesyl pyrophosphate.
- Endomembrane domains
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Internal membranes of the cell such as the nuclear membrane, Golgi and endoplasmic reticulum.
- Exocyst complex
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The exocyst is a large complex of proteins required for polarised exocytosis in eukaryotic cells. It seems to function primarily as a tether, directing secretory vesicles to specific sites on the plasma membrane.
- Coated-pit endocytosis
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The coated pit is a specialized region of the membrane that is coated with clathrin (for stability, to aid the transport process). The coated pit forms a coated vesicle and then loses its clathrin coat.
- Clathrin adaptor proteins
-
Proteins that recruit clathrin to membranes and concentrate specific transmembrane proteins in clathrin-coated areas of the membrane.
- Apoptosome
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A caspase-activating complex that is formed when cytochrome c is released from mitochondria. It initiates oligomerization of APAF1, which binds procaspase 9 and thereby initiates the caspase cascade that leads to programmed cell death.
- Innate immune signalling
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The innate immune system includes phagocytes, natural killer cells, the complement system and other non-specific components. It protects against infections using mechanisms that exist before infection, providing a rapid response to microbes that is essentially the same regardless of the type of infection.
- Myristoylated
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Refers to the accession of fatty moieties that allow association with the inner layer of the plasma membrane.
- X-linked lymphoproliferative syndrome
-
This is a rare immunodeficiency disease characterized by fatal or near-fatal Epstein–Barr virus-induced infectious mononucleosis in childhood, subsequent hypogammaglobulinaemia and a markedly increased risk of lymphoma or other lymphoproliferative diseases.
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Bodemann, B., White, M. Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat Rev Cancer 8, 133–140 (2008). https://doi.org/10.1038/nrc2296
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DOI: https://doi.org/10.1038/nrc2296
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