Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cho, Hee Jun; Kim, Jong-Tae; Baek, Kyoung Eun; Kim, Bo Yeon; Lee, Hee Gu

doi:10.3390/cells8091037

Cited by 42 publications

(36 citation statements)

References 87 publications

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“…RhoGDIs bind to GDP-bound Rho GTPases and regulate their spatiotemporal activity. In addition, their activity is regulated by post-translational modifications (PTMs), including lipid modification, phosphorylation, ubiquitination, and sumoylation, which lead to changes in cell behavior [4].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Rho GTPases in Human Cancers

Jung

Yoon

Lim

et al. 2020

Cancers

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Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of Rho GTPases in Human Cancers

Jung

Yoon

Lim

et al. 2020

Cancers

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“…According to current views, the expression level of small GTPases of the RhoA-family is not rate limiting for their respective activity. Rather, the activation state depends on the controlling GEFs, GAPs and GDIs in the cellular context [62]. In support of this notion it has been reported that the levels of activated Rac1 are reduced in immune cells of the Vav2 knockout mutant, while its protein levels are unchanged.…”

Section: Discussionmentioning

confidence: 90%

Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro

Wegrzyn

Tedford

et al. 2020

IJMS

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Vav proteins activate GTPases of the RhoA subfamily that regulate the cytoskeleton and are involved in adhesion, migration, differentiation, polarity and the cell cycle. While the importance of RhoA GTPases for neuronal morphology is undisputed, their regulation is less well understood. In this perspective, we studied the consequences of the deletion of Vav2, Vav3 and Vav2 and 3 (Vav2−/−, Vav3−/−, Vav2−/−/3−/−) for the development of embryonic hippocampal neurons in vitro. Using an indirect co-culture system of hippocampal neurons with primary wild-type (WT) cortical astrocytes, we analysed axonal and dendritic parameters, structural synapse numbers and the spontaneous network activity via immunocytochemistry and multielectrode array analysis (MEA). Here, we observed a higher process complexity in Vav3−/−, but not in Vav2−/− neurons after three and five days in vitro (DIV). Furthermore, an enhanced synapse formation was observed in Vav3−/− after 14 days in culture. Remarkably, Vav2−/−/3−/− double knockout neurons did not display synergistic effects. Interestingly, these differences were transient and compensated after a cultivation period of 21 days. Network analysis revealed a diminished number of spontaneously occurring action potentials in Vav3−/− neurons after 21 DIV. Based on these results, it appears that Vav3 participates in key events of neuronal differentiation.

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“…Importantly, all three cell lines showed strong inhibition of cell migration and invasion pathways ( Figure 3 A), supporting our previous results [ 12 ]. This was most likely driven by the loss of HOTAIR and RhoGDI signalling ( Figure 3 B), with both pathways implicated in the regulation of cell migration and invasion [ 35 , 36 , 37 , 38 ]. As implicated above, the STAT3 pathway was differentially regulated across each cell line, with inhibition seen in MSTO-211H, while VMC23 and REN cells saw increasing activity trends ( Figure 3 B).…”

Section: Resultsmentioning

confidence: 99%

YB-1 Knockdown Inhibits the Proliferation of Mesothelioma Cells through Multiple Mechanisms

Johnson

Schelch

Lai

et al. 2020

Cancers

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Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein that has been shown to regulate proliferation, invasion and metastasis in a variety of cancer types. We previously demonstrated that YB-1 is overexpressed in mesothelioma cells and its knockdown significantly reduces tumour cell proliferation, migration, and invasion. However, the mechanisms driving these effects are unclear. Here, we utilised an unbiased RNA-seq approach to characterise the changes to gene expression caused by loss of YB-1 knockdown in three mesothelioma cell lines (MSTO-211H, VMC23 and REN cells). Bioinformatic analysis showed that YB-1 knockdown regulated 150 common genes that were enriched for regulators of mitosis, integrins and extracellular matrix organisation. However, each cell line also displayed unique gene expression signatures, that were differentially enriched for cell death or cell cycle control. Interestingly, deregulation of STAT3 and p53-pathways were a key differential between each cell line. Using flow cytometry, apoptosis assays and single-cell time-lapse imaging, we confirmed that MSTO-211H, VMC23 and REN cells underwent either increased cell death, G1 arrest or aberrant mitotic division, respectively. In conclusion, this data indicates that YB-1 knockdown affects a core set of genes in mesothelioma cells. Loss of YB-1 causes a cascade of events that leads to reduced mesothelioma proliferation, dependent on the underlying functionality of the STAT3/p53pathways and the genetic landscape of the cell.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cited by 42 publications

References 87 publications

Dysregulation of Rho GTPases in Human Cancers

Dysregulation of Rho GTPases in Human Cancers

Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro

YB-1 Knockdown Inhibits the Proliferation of Mesothelioma Cells through Multiple Mechanisms

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