Regulation of the Small GTPase Ras and Its Relevance to Human Disease

Kulhanek, Kayla; Roose, Jeroen P.; Rubio, Ignacio

doi:10.1007/978-1-0716-1190-6_2

Cited by 5 publications

(4 citation statements)

References 165 publications

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“…Like many other GTPases, Rac1 switches between an inactive GDP-bound and an active GTP-bound state during signal transduction [ 32 ] ( Figure 2 c). The protein is involved in a wide range of cellular and physiological processes via a multiplicity of protein partners, among which a variety of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) essential to control Rac1 activity [ 33 ].…”

Section: Rac1 Structure and Functionmentioning

confidence: 99%

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Sauzeau

Beignet²,

Bailly

2022

Biomedicines

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Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them—NSC23766 and EHT 1864—have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.

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Section: Rac1 Structure and Functionmentioning

confidence: 99%

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Sauzeau

Beignet²,

Bailly

2022

Biomedicines

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“…In normal cells, Ras cycles between RasGDP ( off ) and RasGTP ( on ) states at regulated rates. Ras’ intrinsic GTPase activity normally secures efficient conversion to the off state, enhanced by RasGAPs (Ras GTPase Activating Proteins) ( Supplemental Figure S1A ) (Ksionda et al, 2013; Kulhanek et al, 2021). RasGRP, SOS, and other RasGEFs (Ras guanine nucleotide exchange factors) catalyze nucleotide exchange on Ras, which then rebinds free GTP or GDP in the cell.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, over-expression of the Ras activator RasGRP1 (Ras guanine nucleotide releasing protein 1) frequently occurs in T-ALL (Hartzell et al, 2013) and is mutually exclusive with somatic mutations in RAS (Dail et al, 2010). The biochemical impacts of this collection of genetic lesions, such as the amplitude and duration of Ras signals or the cycling patterns through the RasGDP (off) -RasGTP (on) states, are well-documented (Supplemental Figure S1A) (Ksionda et al, 2013;Kulhanek et al, 2021;Mues and Roose, 2016). Here, we focused on two distinct Ras pathway lesions, induced expression of KRas G12D preprint (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions

Karra,

Finger,

Shechtman

et al. 2023

Preprint

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Normal hematopoiesis requires constant prolific production of different blood cell lineages by multipotent hematopoietic stem cells (HSC). Stem- and progenitor- cells need to balance dormancy with proliferation. How genetic alterations impact frequency, lineage potential, and metabolism of HSC is largely unknown. Here, we compared induced expression of KRASG12Dor RasGRP1 to normal hematopoiesis. At low-resolution, both Ras pathway lesions result in skewing towards myeloid lineages. Single-cell resolution CyTOF proteomics unmasked an expansion of HSC- and progenitor- compartments for RasGRP1, contrasted by a depletion for KRASG12D. SCENITH™ quantitates protein synthesis with single-cell precision and corroborated that immature cells display low metabolic SCENITH™ rates. Both RasGRP1 and KRASG12Delevated mean SCENITH™ signals in immature cells. However, RasGRP1-overexpressing stem cells retain a metabolically quiescent cell-fraction, whereas this fraction diminishes for KRASG12D. Our temporal single cell proteomics and metabolomics datasets provide a resource of mechanistic insights into altered hematopoiesis at single cell resolution.

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“…Изучение жизненного цикла ВГС показало, что он может высвобождаться из клетки в составе экзосом, пройдя эндосомальный путь [43,44]. В прохождении этого пути участвуют две клеточные системы -ESCRT и комплекс белков семейства Rab [45][46][47][48]. Активное участие белков семейства Rab наводит на мысль о возможном получении ингибиторов, которые могут подавить или блокировать ВГС-инфекцию.…”

Section: экзосомы и вирус гепатита вunclassified

Exosomes in the life cycle of viruses and the pathogenesis of viral infections

Кущ¹,

Ivanov²

2023

Problems of Virology

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Exosomes are extracellular vesicles of endosomal origin, with a bilayer membrane, 30160 nm in diameter. Exosomes are released from cells of different origins and are detected in various body fluids. They contain nucleic acids, proteins, lipids, metabolites and can transfer the contents to recipient cells. Exosome biogenesis involves cellular proteins of the Rab GTPase family and the ESCRT system, which regulate budding, vesicle transport, molecule sorting, membrane fusion, formation of multivesicular bodies and exosome secretion. Exosomes are released from cells infected with viruses and may contain viral DNA and RNA, as well as mRNA, microRNA, other types of RNA, proteins and virions. Exosomes are capable of transferring viral components into uninfected cells of various organs and tissues. This review analyzes the impact of exosomes on the life cycle of widespread viruses that cause serious human diseases: human immunodeficiency virus (HIV-1), hepatitis B virus, hepatitis C virus, SARS-CoV-2. Viruses are able to enter cells by endocytosis, use molecular and cellular pathways involving Rab and ESCRT proteins to release exosomes and spread viral infections. It has been shown that exosomes can have multidirectional effects on the pathogenesis of viral infections, suppressing or enhancing the course of diseases. Exosomes can potentially be used in noninvasive diagnostics as biomarkers of the stage of infection, and exosomes loaded with biomolecules and drugs - as therapeutic agents. Genetically modified exosomes are promising candidates for new antiviral vaccines.

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Regulation of the Small GTPase Ras and Its Relevance to Human Disease

Cited by 5 publications

References 165 publications

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions

Exosomes in the life cycle of viruses and the pathogenesis of viral infections

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