R‐Ras promotes tumor growth of cervical epithelial cells

Rincón-Arano, B S Héctor; Rosales, Ricardo; Mora, Nancy; Rodriguez-Castañeda, B S Armando; Rosales, Carlos

doi:10.1002/cncr.11093

Cited by 37 publications

(27 citation statements)

References 40 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was also observed in cervical epithelial cells expressing activated R-Ras (87L; Rincon-Arano et al, 2003). However, in these assays, a directional signal is provided such that cells migrate toward collagen, making this migration different from random migration.…”

Section: R-ras Regulates Random Migration Across Collagenmentioning

confidence: 77%

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

Wozniak

Kwong

Chodniewicz

et al. 2005

MBoC

View full text Add to dashboard Cite

Although it is known that the spatial coordination of Rac and Rho activity is essential for cell migration, the molecular mechanisms regulating these GTPases during migration are unknown. We found that the expression of constitutively activated R-Ras (38V) blocked membrane protrusion and random migration. In contrast, expression of dominant negative R-Ras (41A) enhanced migrational persistence and membrane protrusion. Endogenous R-Ras is necessary for cell migration, as cells that were transfected with siRNA for R-Ras did not migrate. Expression of R-Ras (38V) decreased Rac activity and increased Rho activity around the entire cell periphery, whereas expression of dominant negative R-Ras (41A) showed the converse, suggesting that R-Ras can spatially activate Rho and inactivate Rac. Consistent with this role, endogenous R-Ras localized and was preferentially activated at the leading edge of migratory cells in response to adhesion. The effects of R-Ras on cell migration are mediated by PI3-Kinase, as an effector mutant that uncouples PI3-Kinase binding from R-Ras (38V) rescued migration. From these data, we hypothesize that R-Ras plays a key role in cell migration by locally regulating the switch from Rac to Rho activity after membrane protrusion and adhesion.

show abstract

Section: R-ras Regulates Random Migration Across Collagenmentioning

confidence: 77%

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

Wozniak

Kwong

Chodniewicz

et al. 2005

MBoC

View full text Add to dashboard Cite

show abstract

“…To determine whether epithelial cells expressing K1 exhibit increased tumorigenic potential in mice, we used the human C33A cervical carcinoma cell line, which is human papillomavirus-negative. C33A cells by themselves are tumorigenic in nude mice (40), and we wanted to determine whether the introduction of K1 in these cells could enhance the tumorigenicity and/or angiogenic nature of these tumors.…”

Section: Resultsmentioning

confidence: 99%

Immortalization of Primary Endothelial Cells by the K1 Protein of Kaposi's Sarcoma–Associated Herpesvirus

et al. 2006

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3V-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size. (Cancer Res 2006; 66(7): 3658-66)

show abstract

“…Nevertheless, activated forms of R-Ras have been linked to cell transformation (Cox et al, 1994;Jeong et al, 2005;Keely et al, 1999;Nishigaki et al, 2005;Osada et al, 1999;Rincon-Arano et al, 2003;Saez et al, 1994;Zou et al, 2002). Given recent data that EphB2 has tumor suppressor activity in prostate and colorectal cancer Huusko et al, 2004), is tempting to speculate that Eph receptors may exert anti-tumorigenic effects at least in part by negatively regulating R-Ras.…”

Section: Discussionmentioning

confidence: 99%

Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion

Dail

Richter

Godement

et al. 2006

Journal of Cell Science

View full text Add to dashboard Cite

Eph receptor tyrosine kinases regulate the spatial organization of cells within tissues. Central to this function is their ability to modulate cell shape and movement in response to stimulation by the ephrin ligands. The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility. Here, we further characterize the role of R-Ras downstream of both EphA and EphB receptors. Our data show that besides inhibiting R-Ras function through phosphorylation, Eph receptors can reduce R-Ras activity through the GTPase-activating protein, p120RasGAP. By using R-Ras mutants that cannot be inactivated by p120RasGAP and/or cannot be phosphorylated at tyrosine 66, we show that the two forms of R-Ras negative regulation - through increased GTP hydrolysis and phosphorylation - differentially contribute to various ephrin-mediated responses. Retraction of the COS cell periphery depends only on R-Ras inactivation through p120RasGAP. By contrast, both reduced R-Ras GTP levels and tyrosine 66 phosphorylation contribute to the ephrin inhibitory effects on COS cell migration and to ephrin-dependent growth cone collapse in primary neurons. Therefore, Eph receptors can regulate R-Ras in two different ways to achieve cell repulsion.

show abstract

R‐Ras promotes tumor growth of cervical epithelial cells

Cited by 37 publications

References 40 publications

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

Immortalization of Primary Endothelial Cells by the K1 Protein of Kaposi's Sarcoma–Associated Herpesvirus

Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion

Contact Info

Product

Resources

About