The RAL signaling network: Cancer and beyond

Apken, Lisa H.; Oeckinghaus, Andrea

doi:10.1016/bs.ircmb.2020.10.005

Cited by 13 publications

(17 citation statements)

References 355 publications

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“…Several of these interactions are illustrated in Figure 1 . Starting from the N terminus, Rlip has a region which interacts with the AP2 clathrin adapter complex and with ARNO, proteins which facilitate endocytosis and cell spreading/migration, respectively [ 15 , 16 ]. Moving in the N→C direction, next comes a short region that binds R-Ras, an interaction which contributes to ARNO activation.…”

Section: Rlip Structure and Functionmentioning

confidence: 99%

“…Encompassing both the AP2/ARNO interaction region and the R-Ras interaction residues is a region shown to bind Epsin, an interaction which is also thought to regulate cell migration, along with the shutdown of clathrin-dependent endocytosis during mitosis [ 17 , 18 ]. We then encounter the RhoGAP domain, which interacts with the Rho family GTPases Rac1 and Cdc42, proteins which regulate cytoskeletal dynamics, migration, cell cycling, and clathrin-dependent endocytosis, among a wide array of other functions [ 16 , 19 , 20 , 21 ]. This is followed by the Ral binding domain through which Rlip carries out effector functions downstream of both RalA and RalB [ 15 ].…”

Section: Rlip Structure and Functionmentioning

confidence: 99%

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Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Hindle

Singh

Pradeepkiran

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.

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Section: Rlip Structure and Functionmentioning

confidence: 99%

Section: Rlip Structure and Functionmentioning

confidence: 99%

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Hindle

Singh

Pradeepkiran

et al. 2022

IJMS

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“…Previous studies indicated that Ral GTPases harbor activating mutations in about 25% of all human cancers, making them the most frequently mutated oncogenes [6]. Various physiological functions have been associated with Ral GTPases, including neuronal plasticity, immune response, and glucose and lipid homeostasis [7]. Ral GTPases include RALA and RALB.…”

Section: Introductionmentioning

confidence: 99%

“…Numerous clinical and experimental studies have reported that RALA is a significant driver of diverse biological processes like proliferation, migration, and invasion of various human cancers, including skin, lung, pancreatic, colon, prostate, and bladder cancers [8]. Several preliminary studies suggested that RALA can participate in immune cell differentiation and the regulation of related processes [7,9]. Low expression of RALA affects the recognition and migration of NK cells, reduces the toxicity of NK cells, interferes with the maintenance of NK cell homeostasis, and inhibits the immune surveillance function of NK cells [10].…”

Section: Introductionmentioning

confidence: 99%

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma

Fan

Zhu

et al. 2023

BioMed Research International

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Background. Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Methods. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. Results. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. Conclusions. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

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“…Activation of RalA and RalB is mediated by guanine nucleotide exchange factors (RalGEFs). There are eight RalGEFs reported for humans, and four of them, RALGDS, Rgl1, Rgl2 and Rgl3, have a Ras-association (RA) domain (in this work, we generically call it Ras Binding Domain (RBD)) responsible for Ras-binding (Apken and Oeckinghaus, 2021). RALGDS was the first to be identified as a Ras effector among these RalGEFs and is by far the most studied (Neel et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the complex of oncogenic KRas4B^G12Vand Rgl2, a RalA/B activator

Tariq

Ikeya

Togashi

et al. 2022

Preprint

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Ras is a small GTPase that regulates fundamental cellular activities. Activated Ras transduces the signalling by directly interacting with effector proteins. About a quarter of total human cancers carry mutations in Ras isoforms, and hence understanding the structure and molecular interactions of Ras with effector proteins is of vital importance. Accumulating evidence suggests that small GTPases, RalA and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We, therefore, studied the interaction between human K-Ras4B and the Ras binding domain (RBD) of Rgl2 (Rgl2RBD) because, among RBD-containing RalGEFs, Rgl2 is predicted to be most significantly in complex with Ras in over 29 human tissues [Catozzi S, Halasz M, & Kiel C (2021) Predicted 'wiring landscape' of Ras-effector interactions in 29 human tissues. NPJ Syst Biol Appl 7(1):10]. We show that the affinity between K-Ras4B and Rgl2RBD is increased when K-Ras4B carries oncogenic mutation G12V. The crystal structure of the K-Ras4BG12V: Rgl2RBD complex shows that a heterotetramer is formed where the Switch I and Switch II regions of a single K-RasG12V molecule interact with two separate Rgl2RBD. This structural arrangement is highly similar to the H-RasE31K:RALGDS crystal structure and is distinct from the well-characterised Ras:RAFRBD complexes. Importantly, the G12V mutation was found at the dimer interface of K-Ras4BG12V with its partner. Solution state NMR and mass photometry analyses support the heterotetramer formation in solution. Our study reveals a distinct mode of Ras:effector complex formation by RalGEFs, and points to a possibility that K-Ras4BG12V oncogenicity originates from the formation of a stable complex with Rgl2.

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The RAL signaling network: Cancer and beyond

Cited by 13 publications

References 355 publications

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma

Structural insights into the complex of oncogenic KRas4B^G12Vand Rgl2, a RalA/B activator

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The RAL signaling network: Cancer and beyond

Cited by 13 publications

References 355 publications

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma

Structural insights into the complex of oncogenic KRas4BG12Vand Rgl2, a RalA/B activator

Contact Info

Product

Resources

About

Structural insights into the complex of oncogenic KRas4B^G12Vand Rgl2, a RalA/B activator