Rac1 GTPase: A “Rac” of All Trades

Bosco, Emily E.; Mulloy, James C.; Zheng, Yi

doi:10.1007/s00018-008-8552-x

Cited by 301 publications

(265 citation statements)

References 64 publications

(55 reference statements)

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“…47) and RAC1 (Ras-related C3 botulinum toxin substrate 1), a member of the RAS superfamily of small GTP-binding proteins that are implicated in the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases (reviewed in Ref. 48). Neither JUN nor RAC1 contain predicted miR-122 target sites; however, both engage in functional interactions with several miR-122 targets identified in our screen.…”

Section: Resultsmentioning

confidence: 99%

Two-tiered Approach Identifies a Network of Cancer and Liver Disease-related Genes Regulated by miR-122

Boutz

Collins

Suresh

et al. 2011

Journal of Biological Chemistry

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MicroRNAs function as important regulators of gene expression and are commonly linked to development, differentiation, and diseases such as cancer. To better understand their roles in various biological processes, identification of genes targeted by microRNAs is necessary. Although prediction tools have significantly helped with this task, experimental approaches are ultimately required for extensive target search and validation. We employed two independent yet complementary high throughput approaches to map a large set of mRNAs regulated by miR-122, a liver-specific microRNA implicated in regulation of fatty acid and cholesterol metabolism, hepatitis C infection, and hepatocellular carcinoma. The combination of luciferase reporterbased screening and shotgun proteomics resulted in the identification of 260 proteins significantly down-regulated in response to miR-122 in at least one method, 113 of which contain predicted miR-122 target sites. These proteins are enriched for functions associated with the cell cycle, differentiation, proliferation, and apoptosis. Among these miR-122-sensitive proteins, we identified a large group with strong connections to liver metabolism, diseases, and hepatocellular carcinoma. Additional analyses, including examination of consensus binding motifs for both miR-122 and target sequences, provide further insight into miR-122 function. MicroRNAs (miRNAs)4 are small (20 -24 nt) endogenously expressed noncoding RNAs that regulate the translational efficiency and/or degradation of specific mRNAs. First discovered in Caenorhabditis elegans (1), miRNAs have since been identified in a diverse set of eukaryotic organisms as well as viruses, with over 700 miRNAs currently identified in humans (2). miRNAs function via the RNAi pathway, guiding the RNAinduced silencing complex to mRNAs by Watson-Crick base pairing between the miRNA and target mRNA (reviewed in Ref.3). The resulting interaction leads to translational repression of the mRNA, although how this repression is achieved remains unclear. Several mechanisms have been proposed (reviewed in Ref. 4), and many questions remain; however, it is clear that sequence complementarity lies at the heart of miRNA function. In animals, sequence complementarity between an miRNA and its target mRNA is rarely perfect. The vast majority of binding sites contain mismatches between strands, and these mismatches have been shown to play an important functional role in target repression (5, 6). Imperfect complementarity allows for a greater variability of target sequences, thus increasing the number of potential binding sites for a given miRNA, with estimates of 300 -400 targets on average per miRNA (7). Although many potential miRNA targets can be identified through predictions, no computational approach is all-inclusive, and even highly conservative predictions must be validated by experimental means to verify functional relevance.Certain miRNAs have caught the attention of scientists due to their strong connections to diseases and cancer. Such is the

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Section: Resultsmentioning

confidence: 99%

Two-tiered Approach Identifies a Network of Cancer and Liver Disease-related Genes Regulated by miR-122

Boutz

Collins

Suresh

et al. 2011

Journal of Biological Chemistry

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“…Like Ras, Rac1 cycles between an active GTP-bound form and an inactive GDP-bound form. The best studied function of the canonical isoform of Rac1 is regulation of cell migration through its control of lamellipodial protrusion (Bosco et al 2009). Additional roles in cell proliferation and the creation of reactive oxygen species have also been uncovered (Kheradmand et al 1998;Bosco et al 2009).…”

Section: Rac1mentioning

confidence: 99%

“…The best studied function of the canonical isoform of Rac1 is regulation of cell migration through its control of lamellipodial protrusion (Bosco et al 2009). Additional roles in cell proliferation and the creation of reactive oxygen species have also been uncovered (Kheradmand et al 1998;Bosco et al 2009). Rac1 has been shown to activate transcription by NFkB as well as the AKT kinase, both important pathways in many cancers (Keely et al 1997;Perona et al 1997).…”

Section: Rac1mentioning

confidence: 99%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

721

667

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Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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“…In response to extracellular signals, the active Rac1-GTP can interact with different effectors and activate multiple intracellular signals that regulate actin cytoskeletal reorganization, vesicle trafficking, and cell migration. 13 In OSCC, elevated expression of Rac1 is found in tumor lesions and its activity can be upregulated by Vav2, correlating with the enhanced invasive properties. 9,14 Differing from Rac1 as an enzyme, cortactin is an adaptor protein that binds and activates the Arp2/3 complex, functioning to regulate the formation of branched actin networks.…”

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confidence: 99%

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. Oral squamous cell carcinoma (OSCC) is the most common malignancy occurring in the oral cavity that usually arises from the buccal mucosa and tongue. During the tumor progression, OSCC cells gradually spread and invade to neighboring tissues, including the nasal cavity or the maxillary facial structures, and eventually metastasize to neck lymph nodes and distant organs. 1 Similar to other malignant diseases, tumor metastasis is a great challenge for the treatment of OSCC. This notion is supported by the fact that only 50% of diagnosed OSCC patients can survive for 5 years, and this is mainly because OSCC patients continue to die from tumor relapse at regional or distant sites. 2 Despite advances in diagnosis and therapy in past decades, the promising strategy for treating patients with metastatic OSCC is still underdeveloped, due in part to the limited understanding of the molecular events involved in invasion and metastasis of OSCC. The underlying molecular basis of OSCC metastasis deserves intensive study.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase and functionally involves the regulatory processes of multiple cellular events, including adhesion, migration, invasion, prolifer...

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Rac1 GTPase: A “Rac” of All Trades

Cited by 301 publications

References 64 publications

Two-tiered Approach Identifies a Network of Cancer and Liver Disease-related Genes Regulated by miR-122

Two-tiered Approach Identifies a Network of Cancer and Liver Disease-related Genes Regulated by miR-122

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

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