Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation

Benitah, Salvador Aznar; Valerón, Pilar F.; Aelst, Linda Van; Marshall, Christopher J.; Lacal, Juan Carlos

doi:10.1016/j.bbcan.2004.10.002

Cited by 102 publications

(115 citation statements)

References 103 publications

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“…The primary function of this pathway is the generation of acto-myosin contractile force, which influences behaviors including motility, survival and proliferation. There is a wealth of data implicating Rho GTPases in human cancer (Sahai and Marshall, 2002;Benitah et al, 2004) further suggesting that ROCK1 and ROCK2, as key mediators of Rho signaling, may have important roles (Narumiya et al, 2009). In support of this, preclinical studies have shown beneficial effects of ROCK inhibition on tumor incidence rates, volume, invasiveness and metastasis (Itoh et al, 1999;Somlyo et al, 2000;Nakajima et al, 2003;Ying et al, 2006;Ogawa et al, 2007;Xue et al, 2008).…”

mentioning

confidence: 99%

Activating ROCK1 somatic mutations in human cancer

et al. 2010

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Cancer cells acquire characteristics of deregulated growth, survival and increased metastatic potential. Genetic mutations that provide a selective advantage by promoting these characteristics have been termed 'drivers,' whereas mutations that do not contribute to disease initiation/progression are termed 'passengers.' The advent of high-throughput methodologies has facilitated large-scale screening of cancer genomes and the subsequent identification of novel somatic mutations. Although this approach has generated valuable results, the data remain incomplete until the functional consequences of these mutations are determined to differentiate potential drivers from passengers. ROCK1 is an essential effector kinase downstream of Rho GTPases, an important pathway involved in cell migration. The Cancer Genome Project identified three nonsynonymous mutations in the ROCK1 gene. We now show that these somatic ROCK1 mutations lead to elevated kinase activity and drive actin cytoskeleton rearrangements that promote increased motility and decreased adhesion, characteristics of cancer progression. Mapping of the kinase-interacting regions of the carboxy terminus combined with structural modeling provides an insight into how these mutations likely affect the regulation of ROCK1. Consistent with the frequency of ROCK1 mutations in human cancer, these results support the conclusion that there is selective pressure for the ROCK1 gene to acquire 'driver' mutations that result in kinase activation.

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confidence: 99%

Activating ROCK1 somatic mutations in human cancer

et al. 2010

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“…RhoA is highly overexpressed in several cancers, such as gastric carcinoma and pancreatic, colorectal, lung, and breast tumors (62)(63)(64)(65), but its role in vGPCR-induced tumorigenesis has not yet been clearly established. Instead, it is known that vGPCR activates the small GTPases Rac and Cdc42 and that Rac mediates vGPCR-induced activation of the NFB transcription factor, thus up-regulating the secretion of critical KS cytokines and ultimately paracrine tumorigenesis (28,31).…”

Section: Discussionmentioning

confidence: 99%

“…HO-1 Participates in RhoA-induced Tumorigenesis-RhoA has oncogenic potential, and like HO-1 (8,13,15,60,61), it is overexpressed in several types of cancer (62)(63)(64)(65). To determine whether there is a functional link between RhoA-induced tumorigenesis and HO-1 expression, 1 ϫ 10 6 NIH-RhoAQL cells were injected in the right flank of 10 athymic nude mice.…”

Section: Ho-1 Mediates Vgpcr and Rhoa-induced Vegf-a Expression And Smentioning

confidence: 99%

The Gα12/13 Family of Heterotrimeric G Proteins and the Small GTPase RhoA Link the Kaposi Sarcoma-associated Herpes Virus G Protein-coupled Receptor to Heme Oxygenase-1 Expression and Tumorigenesis

Martín

Tanos

García

et al. 2007

Journal of Biological Chemistry

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“…Much evidence exists linking Rho GTPases to transformation of cells; however, contrary to the Ras gene, activating mutations in Rho genes are rarely found in human cancers (2,3). It seems instead that the expression of Rho GTPases and expression and function of regulators of the Rho subfamily of GTPases are altered during cellular transformation (2,3).…”

mentioning

confidence: 99%

“…RhoA, Rac1, and Cdc42 are the best known members of this family, and they are most often associated with their roles as regulators of cytoskeleton remodeling and as key mediators of the activation of transcription of genes downstream of growth factor receptors (1). Much evidence exists linking Rho GTPases to transformation of cells; however, contrary to the Ras gene, activating mutations in Rho genes are rarely found in human cancers (2,3). It seems instead that the expression of Rho GTPases and expression and function of regulators of the Rho subfamily of GTPases are altered during cellular transformation (2,3).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site

Danek¹,

Tcherkezian²,

Triki

et al. 2007

Journal of Biological Chemistry

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Rho GTPases regulate a multitude of cellular processes from cytoskeletal reorganization to gene transcription and are negatively regulated by GTPase-activating proteins (GAPs). Cdc42 GTPase-activating protein (CdGAP) is a ubiquitously expressed GAP for Rac1 and Cdc42. In this study, we set out to identify CdGAP-binding partners and, using a yeast two-hybrid approach, glycogen synthase kinase 3␣ (GSK-3␣) was identified as a partner for CdGAP. GSK-3 exists in two isoforms, ␣ and ␤, and is involved in regulating many cellular functions from insulin response to tumorigenesis. We show that GSK-3␣ and -␤ interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. We report that the mRNA and protein levels of CdGAP are increased upon serum stimulation and that GSK-3 activity is necessary for the up-regulation of the protein levels of CdGAP but not for the increase in mRNA. We conclude that GSK-3 is an important regulator of CdGAP and that regulation of CdGAP protein levels by serum presents a novel mechanism for cells to control Cdc42/Rac1 GTPase signaling pathways.The Rho subfamily of small GTPases controls a wide variety of cellular functions. RhoA, Rac1, and Cdc42 are the best known members of this family, and they are most often associated with their roles as regulators of cytoskeleton remodeling and as key mediators of the activation of transcription of genes downstream of growth factor receptors (1). Much evidence exists linking Rho GTPases to transformation of cells; however, contrary to the Ras gene, activating mutations in Rho genes are rarely found in human cancers (2, 3). It seems instead that the expression of Rho GTPases and expression and function of regulators of the Rho subfamily of GTPases are altered during cellular transformation (2, 3).Rho GTPases act in a cycle as molecular switches with an active GTP-bound form and an inactive GDP-bound form (1). The GTPase-activating proteins (GAPs) 5 negatively regulate the GTPases by enhancing the hydrolysis of GTP to GDP (1). To date, ϳ70 human genes are predicted to encode for potential RhoGAP proteins (4), which is roughly triple the number of Rho GTPases (1). This lends weight to the notion that regulators like the RhoGAPs tightly control Rho GTPases and lend context-dependent specificity to their processes. Thus, the activity of RhoGAPs must be highly regulated in both spatial and temporal fashions. RhoGAPs are regulated at the protein level by a variety of mechanisms ranging from protein-protein interactions to phosphorylation, lipid interactions, and proteolytic degradation (5).Cdc42 GTPase-activating protein (CdGAP) has been shown to regulate both Cdc42 and Rac1 in vitro and in vivo and exists in two main isoforms: a short form of 820 amino acids containing an N-terminal RhoGAP domain, a central region, and a C-terminal proline-rich region (PRD) (6, 7) and a long isoform comprising the...

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Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation

Cited by 102 publications

References 103 publications

Activating ROCK1 somatic mutations in human cancer

Activating ROCK1 somatic mutations in human cancer

The Gα12/13 Family of Heterotrimeric G Proteins and the Small GTPase RhoA Link the Kaposi Sarcoma-associated Herpes Virus G Protein-coupled Receptor to Heme Oxygenase-1 Expression and Tumorigenesis

Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site

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