RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression

Melzer, Catharina; Hass, Ralf; Lehnert, Hendrik; Ungefroren, Hendrik

doi:10.3390/cells8010021

Cited by 39 publications

(50 citation statements)

References 75 publications

(181 reference statements)

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“…The depletion of Rac1 in Kras-induced pancreatic ductal adenocarcinoma in mice reduces tumor development and prolongs survival [75]. Rac1b, the constitutively active splice variant of Rac1, is highly expressed in colon, lung, and breast cancers, and plays a critical role in different stages of cancer progression [76,77]. Cdc42 expression is also upregulated in many human cancers [78].…”

Section: Altered Expression and Activity Of Rho Gtpases In Human Cancersmentioning

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: Altered Expression and Activity Of Rho Gtpases In Human Cancersmentioning

confidence: 99%

Dysregulation of Rho GTPases in Human Cancers

Jung

Yoon

Lim

et al. 2020

Cancers

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“…In addition, RAC1B differs from RAC1 by the type of upstream activators, binding partners, and downstream effectors/targets, although only few RAC1B-specific target genes have been identified so far. RAC1B has been implicated in tumor progression by its ability to promote cell cycle progression and apoptosis resistance in some cell types, however, its role in other processes driving malignant transformation such as epithelial-mesenchymal transition (EMT), migration/invasion, and metastasis is less clear (for review see [1]).…”

Section: Introductionmentioning

confidence: 99%

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

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“…Rather, lung adenocarcinomas have been reported to up-regulate a spliced variant of RAC1 with a 19amino acid in-frame insertion known as Rac1b, particularly in tumors from smokers and patients who showed node positive disease (Stallings-Mann et al, 2012). Unlike Rac1 point mutants, Rac1b displays both impaired GTP hydrolysis and increased GDP/GTP exchange (Melzer et al, 2019). Inducible expression of Rac1b in the lung epithelium of transgenic mice results in tissue architecture features consistent with activation of EMT, with a concomitant increased expression of mesenchymal markers (e.g., vimentin) and down-regulation of epithelial markers (e.g., E-cadherin).…”

Section: Rac1 Cycling Deregulation: It Never Gets Easier It Just Goementioning

confidence: 99%

Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer

Cooke

Baker

Kazanietz

2020

Front. Cell Dev. Biol.

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Lung cancer is the leading cause of cancer-related deaths worldwide, with nonsmall cell lung cancer (NSCLC) representing ∼85% of new diagnoses. The disease is often detected in an advanced metastatic stage, with poor prognosis and clinical outcome. In order to escape from the primary tumor, cancer cells acquire highly motile and invasive phenotypes that involve the dynamic reorganization of the actin cytoskeleton. These processes are tightly regulated by Rac1, a small G-protein that participates in the formation of actin-rich membrane protrusions required for cancer cell motility and for the secretion of extracellular matrix (ECM)-degrading proteases. In this perspective article we focus on the mechanisms leading to aberrant Rac1 signaling in NSCLC progression and metastasis, highlighting the role of Rac Guanine nucleotide Exchange Factors (GEFs). A plausible scenario is that specific Rac-GEFs activate discrete intracellular pools of Rac1, leading to unique functional responses in the context of specific oncogenic drivers, such as mutant EGFR or mutant KRAS. The identification of dysregulated Rac signaling regulators may serve to predict critical biomarkers for metastatic disease in lung cancer patients, ultimately aiding in refining patient prognosis and decision-making in the clinical setting.

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RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression

Cited by 39 publications

References 75 publications

Dysregulation of Rho GTPases in Human Cancers

Dysregulation of Rho GTPases in Human Cancers

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer

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