The RAL Enigma: Distinct Roles of RALA and RALB in Cancer

Richardson, Dillon S.; Spehar, Jonathan M.; Han, David T.; Chakravarthy, Prathik A.; Sizemore, Steven T.

doi:10.3390/cells11101645

Cited by 9 publications

(3 citation statements)

References 201 publications

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“…Mediated by GAPs and GEFs they shuttle between a GDP-loaded inactive and GTP loaded active form, which binds to downstream effectors. RHO family members mainly co-ordinate cytoskeletal processes necessary for cell migration [ 140 ], while RAL A/B regulate vesicular trafficking and autophagy [ 141 ]. These processes generally support RAS-mediated oncogenesis, although RHO proteins have a dual role and also can suppress tumorigenesis [ 143 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

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Section: Discussionmentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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“…RalGAP in turn regulates, together with the Ral guanine nucleotide exchange factor (RalGEF), the activity of the Ras-like (Ral) proteins RalA and RalB [ 20 ]. Those two highly related G proteins have different subcellular locations, but are both involved in a vast number of central cellular processes, including tumorigenesis [ 21 , 22 ]. Physiologically, RalA is implicated in cellular processes, which depend on directional membrane trafficking, such as cell migration, establishment of cell polarity, neuronal polarity, and ciliogenesis.…”

Section: Discussionmentioning

confidence: 99%

RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia

Christen

Zdora²,

Leschnik

et al. 2023

Genes

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Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype–phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.

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“…The Ral family is a class of low-molecular-weight proteins with 2 forms: inactive Ral-GDP and active Ral-GTP. [31] Ral has 2 homologous isomers, RalA and RalB. RalA is a multifunctional small GTPase that participates in cell material transport, cell proliferation, cell migration, apoptosis, carcinogenesis and actin cytoskeleton remodeling.…”

Section: Introduction Of Tntsmentioning

confidence: 99%

The role of mitochondrial transfer via tunneling nanotubes in the central nervous system: A review

Chen,

Xiao,

2024

Medicine

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Tumour necrosis factor alpha-induced protein 2 (TNFAIP2) is a gene induced by tumor necrosis factor in endothelial cells. TNFAIP2 has important functions in physiological and pathological processes, including cell proliferation, adhesion, migration, angiogenesis, inflammation, tunneling nanotube (TNT) formation and tumorigenesis. Moreover, TNFAIP2 is the key factor in the formation of TNTs. TNTs are related to signal transduction between different cell types and are considered a novel means of cell-to-cell communication. Mesenchymal stem cells (MSCs) are pluripotent cells that exhibit self-renewal, multidirectional differentiation, paracrine function and immune-regulating ability. MSCs can transfer mitochondria through TNTs to improve the functions of target cells. This review revealed that TNFAIP2 promotes the formation of TNTs and that MSCs rely on TNTs for mitochondrial transfer to ameliorate cell dysfunction.

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The RAL Enigma: Distinct Roles of RALA and RALB in Cancer

Cited by 9 publications

References 201 publications

Dynamic regulation of RAS and RAS signaling

Dynamic regulation of RAS and RAS signaling

RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia

The role of mitochondrial transfer via tunneling nanotubes in the central nervous system: A review

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