Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels

Sawada, Junko; Urakami, Takeo; Li, Fangfei; Urakami, Akane; Zhu, Weiquan; Fukuda, Minoru; Li, Dean Y.; Ruoslahti, Erkki; Komatsu, Masanobu

doi:10.1016/j.ccr.2012.06.013

Cited by 94 publications

(168 citation statements)

References 37 publications

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“…Plasma leakage is increased, endothelial cell-cell junctions are disrupted, and VE-cadherin immunostaining is decreased in tumor vessels in R-Ras knockout mice. It was further demonstrated that expression of the constitutively active R-Ras-V38 in confluent endothelial cell cultures induced accumulation of VE-cadherin and ␤-catenin at the cell-to-cell interface, thus improving endothelial barrier function (419). This effect has been ascribed to the suppression of VEcadherin internalization through inhibition of its phosphorylation on Ser665.…”

Section: Ras Proteinsmentioning

confidence: 94%

“…R-Ras, through its interaction with filamin A, is therefore required for maintaining endothelial barrier function. An analysis of tumor blood vessel formation in R-Ras knockout mice has confirmed its critical role in vessel integrity and function and particularly in the regulation of vascular permeability (419). Plasma leakage is increased, endothelial cell-cell junctions are disrupted, and VE-cadherin immunostaining is decreased in tumor vessels in R-Ras knockout mice.…”

Section: Ras Proteinsmentioning

confidence: 99%

“…This effect has been ascribed to the suppression of VEcadherin internalization through inhibition of its phosphorylation on Ser665. Expression of the dominant negative R-Ras-N43 or knockdown of endogenous R-Ras has opposite effects (419).…”

Section: Ras Proteinsmentioning

confidence: 99%

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Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

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Section: Ras Proteinsmentioning

confidence: 94%

Section: Ras Proteinsmentioning

confidence: 99%

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Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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“…Alternatively, the combinatorial inactivation of R-Ras, M-Ras, and Rap1 or the inactivation of an as yet unidentified GTPase could account for the developmental functions of plexins. The GTPase activity of plexins toward R-Ras and M-Ras might also be important at later developmental stages of neuronal development, including dendrite remodeling (14), or under pathophysiological conditions such as tumor angiogenesis, in which active R-Ras has been shown to improve vessel integrity and blood vessel perfusion (39,53).…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian plexins constitute a family of transmembrane receptors for semaphorins and represent critical regulators of various processes during development of the nervous, cardiovascular, skeletal, and renal system. In vitro studies have shown that plexins exert their effects via an intracellular R-Ras/M-Ras GTPase-activating protein (GAP) domain or by activation of RhoA through interaction with Rho guanine nucleotide exchange factor proteins. However, which of these signaling pathways are relevant for plexin functions in vivo is largely unknown. Using an allelic series of transgenic mice, we show that the GAP domain of plexins constitutes their key signaling module during development. Mice in which endogenous Plexin-B2 or Plexin-D1 is replaced by transgenic versions harboring mutations in the GAP domain recapitulate the phenotypes of the respective null mutants in the developing nervous, vascular, and skeletal system. We further provide genetic evidence that, unexpectedly, the GAP domain-mediated developmental functions of plexins are not brought about via R-Ras and M-Ras inactivation. In contrast to the GAP domain mutants, Plexin-B2 transgenic mice defective in Rho guanine nucleotide exchange factor binding are viable and fertile but exhibit abnormal development of the liver vasculature. Our genetic analyses uncover the in vivo contextdependence and functional specificity of individual plexin-mediated signaling pathways during development.neural tube | cerebellum | outflow tract P lexins constitute a family of transmembrane proteins that serve as receptors for semaphorins (1). They function as key regulators of a multitude of developmental processes, including axon guidance, pattern and synapse formation in the nervous system (2), vasculogenesis and angiogenesis (3, 4), and morphogenesis of the heart, kidney, and skeletal system (5). In the adult organism, plexins play crucial roles in the physiology and pathophysiology of the immune and cardiovascular system, as well as in bone homeostasis and in cancer (6-9). Nine plexins have been identified in the mammalian system, which are grouped into four subfamilies, A-D, according to sequence homologies.The activation of plexins by their semaphorin ligands triggers several intracellular signaling cascades, most of which modulate the activity of small GTPases (10). The intracellular domain of all plexins shares homology with GTPase-activating proteins (GAPs) and confers the deactivation of R-Ras, M-Ras, and Rap1 (11-17). The GAP activity toward R-Ras and M-Ras, but not toward Rap1, requires binding of Rnd GTPases to the plexin receptor (11,12,15,16). Plexins of the B-subfamily differ from all other plexins in that they carry a C-terminal PDZ domain interaction motif that mediates a stable interaction with the Rho guanine nucleotide exchange factor (RhoGEF) proteins . Activation of B-plexins by semaphorin ligands results in activation of the RhoGEF proteins and subsequent activation of . This process and the GAP function of B-plexins are independent of each other, becau...

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“…Recently, intensive studies in normal angiogenic development using mouse model systems have revealed the importance of the angiogenic chemokine CXCL12 for the organized development of vessel branching along with neural development (https://intramural.nhlbi.nih.gov/labs/ldbsn/ pages/publications.aspx). Furthermore, Komatsu et al [88] reported the importance of the small-G protein R-Ras for the development of abnormal collateral capillary systems which may play critical roles in the survival of localized tumors by supporting nutrient and oxygen delivery , [89] . Nonetheless, it remains unclear how the tumor cells, which express chemokine receptors, respond to chemokines released from these pathological vessels, which are inherently "leaky".…”

Section: Chemokines and Angiogenesismentioning

confidence: 99%

Chemokines, chemokine receptors and the gastrointestinal system

Miyazaki¹,

Takabe²,

Yeudall³

2013

WJG

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Core tip: The chemokine network makes an attractive target for therapeutic intervention in many tumor types, including those of the gastrointestinal tract. However, we need to define more selective and specific targets, to minimize systemic side effects during treatment. INTRODUCTION Cancer development and progression in the gastrointestinal tractCancer is a disease in which normal cells acquire genetic and epigenetic abnormalities [1,2] , leading to disorientation of conventional processes for the maintenance of normal cell physiology. These aberrant genetic and epigenetic modifications to the normal cell induce abnormal cell motility, proliferation, and survival, eventually enabling these cells to invade into adjacent tissues and even to migrate to regional or distant organs where they may grow continuously as metastatic lesions [3] . For many cancer patients, metastasis is generally the major cause of disease-related death [4,5] . Therefore, it is indispensable to elucidate the basic molecular mechanisms of tumor development to identify effective therapeutic targets, which can possibly reduce the side-effects of treatment, and define useful molecular markers for early detection and prediction of disease course. Especially, the newly emerged concept of personalized medicine may require in-depth assessment of potential therapeutic molecular target(s) in each individual case through analysis of sig- REVIEW Chemokines, chemokine receptors and the gastrointestinal system AbstractThe biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.

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Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels

Cited by 94 publications

References 37 publications

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Genetic dissection of plexin signaling in vivo

Chemokines, chemokine receptors and the gastrointestinal system

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