Ral GTPases and cancer: linchpin support of the tumorigenic platform

Bodemann, Brian O.; White, Michael A.

doi:10.1038/nrc2296

Cited by 204 publications

(233 citation statements)

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“…Ral GTPases are Ras effectors that promote cell proliferation (Bodemann and White, 2008), and have been shown to play a role in polarized trafficking (Shipitsin and Feig, 2004). The GTPase RalA has been shown to cooperate with the EGFR to promote transformation (Lu et al, 2000).…”

Section: Hijacking Of the Domain-identity Machinerymentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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The Epithelial Polarity Program (EPP) adapts and integrates three ancient cellular machineries to construct an epithelial cell. The polarized trafficking machinery adapts the cytoskeleton and ancestral secretory and endocytic machineries to the task of sorting and delivering different plasma membrane (PM) proteins to apical and basolateral surface domains. The domain-identity machinery builds a tight junctional fence (TJ) between apical and basolateral PM domains and adapts ancient polarity proteins and polarity lipids on the cytoplasmic side of the PM, which have evolved to perform a diversity of polarity tasks across cells and species, to provide 'identity' to each epithelial PM domain. The 3D organization machinery utilizes adhesion molecules as positional sensors of other epithelial cells and the basement membrane and small GTPases as integrators of positional information with the activities of the domain-identity and polarized trafficking machineries. Cancer is a disease mainly of epithelial cells (90% of human cancers are carcinomas that derive from epithelial cells) that hijacks the EPP machineries, resulting in loss of epithelial polarity, which often correlates in extent with the aggressiveness of the tumor. Here, we review how the EPP integrates its three machineries and the strategies used by cancer to hijack them.

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Section: Hijacking Of the Domain-identity Machinerymentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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“…RAL proteins mediate various cellular activities, including filopodia formation/membrane ruffling, glycolysis, autophagy, secretion, the maintenance of polarity, apoptosis and transcription [21,26] (Figure 2). Alterations to these activities can lead to tumor invasion, metastasis, altered cellular energy levels, proliferative signaling and resistance to cell death.…”

Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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“…Finally, a dominant inhibitory form of RalA suppresses the transforming activities of both RasH and Raf. These results demonstrate that activation of Ral-GDS and thus its target, Ral, constitutes a distinct downstream signaling pathway from RasH that potentiates oncogenic transformation (Bodemann and White, 2008).…”

Section: Ralgds Pathwaymentioning

confidence: 74%