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Romain Maxime Larive - One of the best experts on this subject based on the ideXlab platform.
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contribution of the r Ras2 gtp binding protein to primary breast tumorigenesis and late stage metastatic disease
Nature Communications, 2014Co-Authors: Enrique De Alava, Mercedes Dosil, Giulia Moriggi, Romain Maxime Larive, Marta Canamero, Mauricio Menachomarquez, Balbino Alarcon, Xos� R. BusteloAbstract:R-Ras2 is a transforming GTPase that shares downstream effectors with Ras Subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss- and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contRast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.
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the Ras like protein r Ras2 tc21 is important for proper mammary gland development
Molecular Biology of the Cell, 2012Co-Authors: Romain Maxime Larive, Enrique De Alava, Marta Canamero, Balbino Alarcon, Antonio Abad, Clara M Cardaba, Teresa Hernandez, Eugenio Santos, Xosé R BusteloAbstract:R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras Subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing β-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2−/− mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contRast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R-Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type–like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process.
Xos� R. Bustelo - One of the best experts on this subject based on the ideXlab platform.
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contribution of the r Ras2 gtp binding protein to primary breast tumorigenesis and late stage metastatic disease
Nature Communications, 2014Co-Authors: Enrique De Alava, Mercedes Dosil, Giulia Moriggi, Romain Maxime Larive, Marta Canamero, Mauricio Menachomarquez, Balbino Alarcon, Xos� R. BusteloAbstract:R-Ras2 is a transforming GTPase that shares downstream effectors with Ras Subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss- and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contRast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.
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f actin dependent translocation of the rap1 gdp gtp exchange factor Rasgrp2
Journal of Biological Chemistry, 2004Co-Authors: Mariia J Caloca, Jose L Zugaza, Miguel Vicentemanzanares, Francisco Sanchezmadrid, Xos� R. BusteloAbstract:Abstract RasGRPs constitute a new group of diacylglycerol-dependent GDP/GTP exchange factors that activate Ras Subfamily GTPases. Despite a common structure, Ras-GRPs diverge in their GTPase specificity, subcellular distribution, and downstream biological effects. The more divergent family member is RasGRP2, a Rap1-specific exchange factor with low affinity toward diacylglycerol. The regulation of RasGRP2 during signal transduction has remained elusive up to now. In this report, we show that the subcellular localization of Ras-GRP2 is highly dependent on actin dynamics. Thus, the induction of F-actin by cytoskeletal regulators such as Vav, Vav2, Dbl, and Rac1 leads to the shift of RasGRP2 from the cytosol to membrane ruffles and its co-localization with F-actin. Treatment of cells with cytoskeletal disrupting drugs abolishes this effect, leading to an abnormal localization of RasGRP2 in cytoplasmic clusters of actin. The use of Rac1 effector mutants indicates that the RasGRP2 translocation is linked exclusively to actin polymerization and is independent of other pathways such as p21-activated kinase JNK, or superoxide production. Biochemical experiments demonstrate that the translocation of RasGRP2 to membrane ruffles is mediated by the direct association of this protein with F-actin, a property contained within its 150 first amino acids. Finally, we show that the RasGRP2/F-actin interaction promotes the regionalized activation of Rap1 in juxtamembrane areas of the cell. These results reveal a novel function of the actin cytoskeleton in mediating the spatial activation of Ras Subfamily GTPases through the selective recruitment of GDP/GTP exchange factors.
Xosé R Bustelo - One of the best experts on this subject based on the ideXlab platform.
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the Ras like protein r Ras2 tc21 is important for proper mammary gland development
Molecular Biology of the Cell, 2012Co-Authors: Romain Maxime Larive, Enrique De Alava, Marta Canamero, Balbino Alarcon, Antonio Abad, Clara M Cardaba, Teresa Hernandez, Eugenio Santos, Xosé R BusteloAbstract:R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras Subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing β-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2−/− mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contRast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R-Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type–like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process.
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Signal transduction elements of TC21, an oncogenic member of the R-Ras Subfamily of GTP-binding proteins
Oncogene, 1999Co-Authors: Nieves Movilla, Piero Crespo, Xosé R BusteloAbstract:TC21 is a Ras-like GTPase with high oncogenic potential that is found mutated in some human tumors and overexpressed in breast cancer cell lines. We have conducted cellular and biochemical studies in order to understand the role of this protein in signal transduction and to unveil the signaling elements that participate in the TC21 pathway. Using gene transfer experiments, we demonstrate here that the TC21 oncogene can induce both cellular transformation in mouse fibroblasts and neuronal-like differentiation in rat PC12 cells. Interestingly, the proto-oncogenic version of TC21 shows also a lower, but significant, activity in both biological processes. We also demonstrate that the similarity of the cellular responses induced by TC21 and Ras derive from the utilization of overlapping pathways. Thus, the exchange of guanosine nucleotides in wild type TC21 is catalyzed by Ras exchange factors. Moreover, TC21 binds physically to c-Raf-1 in a GTP-dependent manner. Finally, overexpression of TC21^G23V in NIH3T3 cells results in the activation of c-Raf-1 and the MAPK and the JNK branches of serine/threonine cascades. From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signaling elements of the Ras oncogenic pathway.
Andrew M. Chan - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding
2016Co-Authors: Mingfei Yan, Yihe Guo, Yuhong Chen, Cheryl A. Hillery, Andrew M. ChanAbstract:The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-Subfamily of small guanosine-5’-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (RRas−/−). An examination of the lymphoid organs of RRas−/− mice revealed a 40 % reduction in the cellularity of the peripheral lymph nodes. Morphologi-cally, the high endothelial venules of RRas−/−mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from RRas−/−mice had approximately 42 % lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects inRRas−/ − T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, RRas−/ − T cells had approximately 14.5 % attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with RRas−/ − T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response
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R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding
2016Co-Authors: Xiaocai Yan, Mingfei Yan, Yihe Guo, Gobind Singh, Yuhong Chen, Demin Wang, Cheryl A. Hillery, Andrew M. ChanAbstract:The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-Subfamily of small guanosine-5’-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (RRas−/−). An examination of the lymphoid organs of RRas−/− mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of RRas−/− mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from RRas−/− mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in RRas−/− T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, RRas−/− T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with RRas−/− T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response.
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r Ras3 m Ras induces neuronal differentiation of pc12 cells through cell type specific activation of the mitogen activated protein kinase cascade
Molecular and Cellular Biology, 2002Co-Authors: Alec C Kimmelman, Nelson Nunez Rodriguez, Andrew M. ChanAbstract:R-Ras3/M-Ras is a novel member of the Ras Subfamily of GTP-binding proteins which has a unique expression pattern highly restricted to the mammalian central nervous system. In situ hybridization using an R-Ras3 cRNA probe revealed high levels of R-Ras3 transcripts in the hippocampal region of the mouse brain as well as a pattern of expression in the cerebellum that was distinct from that of H-Ras. We found that R-Ras3 was activated by nerve growth factor (NGF) and basic fibroblast growth factor as well as by the guanine nucleotide exchange factor GRP but not by epidermal growth factor. Ectopic expression of either R-Ras3 or GRP in PC12 cells induced efficient neuronal differentiation. The ability of NGF as well as GRP to promote differentiation of PC12 cells was attenuated by an R-Ras3 dominant-negative mutant. Furthermore, the biological action of R-Ras3 in PC12 cells was dependent on the mitogen-activated protein kinase (MAPK). Interestingly, whereas R-Ras3 was unable to mediate efficient activation of MAPK activity in NIH 3T3 cells, it was able to do so in PC12 cells. This cell-type specificity is in stark contRast to that of H-Ras, which can stimulate the MAPK pathway in both cell types. Indeed, this pattern of MAPK activation could be explained by the fact that R-Ras3 was unable to activate c-Raf, while it bound and stimulated the neuronal Raf isoform, B-Raf, in PC12 cells. Thus, R-Ras3 is implicated in a novel pathway of neuronal differentiation by coupling specific trophic factors to the MAPK cascade through the activation of B-Raf.
Balbino Alarcon - One of the best experts on this subject based on the ideXlab platform.
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contribution of the r Ras2 gtp binding protein to primary breast tumorigenesis and late stage metastatic disease
Nature Communications, 2014Co-Authors: Enrique De Alava, Mercedes Dosil, Giulia Moriggi, Romain Maxime Larive, Marta Canamero, Mauricio Menachomarquez, Balbino Alarcon, Xos� R. BusteloAbstract:R-Ras2 is a transforming GTPase that shares downstream effectors with Ras Subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss- and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contRast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.
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the Ras like protein r Ras2 tc21 is important for proper mammary gland development
Molecular Biology of the Cell, 2012Co-Authors: Romain Maxime Larive, Enrique De Alava, Marta Canamero, Balbino Alarcon, Antonio Abad, Clara M Cardaba, Teresa Hernandez, Eugenio Santos, Xosé R BusteloAbstract:R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras Subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing β-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2−/− mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contRast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R-Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type–like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process.
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RRas2, RhoG and T-cell phagocytosis
Small GTPases, 2012Co-Authors: Balbino Alarcon, Nuria Martínez-martínAbstract:Activating mutations and overexpression of classical Ras Subfamily members (K-Ras, N-Ras and H-Ras) have been widely investigated as key events in the development of human cancers. The role in cancer of its closest relatives, the Ras-related (RRas) Subfamily members, has been less studied despite the fact that one of its members (TC21 or RRas2) is strongly transforming in vitro. Nevertheless, and in spite the paucity of publications, several studies have shown that wild type TC21 is overexpressed in different types of carcinomas and lymphomas. If the study of RRas members in cancer is still in its infancy, their role in physiological functions is even behind. For instance, T and B cell immunologists still use the vague term “Ras activation” without indication of what Ras family molecule is indeed intervening. In this view, we discuss the participation of TC21 in the specific process of T cell antigen receptor internalization from the immunological synapse and acquisition of membrane fragments from the antigen presenting cells by phagocytosis.
