Shuh Narumiya

..Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2...

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..p160ROCK induces focal adhesions and stress fibers by activating integrin and clustering them by the use of myosin-based contractility...

..Thus, Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia...

..Here I summarize our findings obtained by these and other studies. These findings suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of certain immunological disorders...

..We also discuss redundancy of dc42 and Cdc42-related GTPase(s) and potential mechanisms of chromosome instability in cancer...

..Recent work indicates that they may function during both spindle orientation and chromosome congression. However, their involvement is cell-type-specific, raising arguments for and against a mitotic role for Rho GTPases...

..Thus, a new concept on the role of prostanoids in inflammation has arisen from studies using the receptor knockout mice...

..Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA(2) and PGF(2alpha) formed under systemic inflammatory conditions...

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..However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload-induced cardiac hypertrophy using mice lacking each of their receptors...

..These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo...

..Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis...

..These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration...

..These results suggest that Rho GTPases function in G2/M transition of mammalian cells by mediating multiple signaling pathways converging to centrosomal activation of Aurora-A...

..These results suggest that PGE2 produced by dendritic cells in the lymph nodes acts on EP1 in naive T cells to promote Th1 differentiation...

..However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation...

..These results suggest that Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis...

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..Given overexpression of c-Src in various cancers, these findings suggest that Rho-mDia1 signaling facilitates malignant transformation and invasion by manipulating the actin cytoskeleton and targeting Src to the cell periphery...

..These results clearly indicate that the PGI(2)-IP system together with the complement system plays a key role in exudate formation in zymosan-induced pleurisy...

..These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses...

..Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway...

..Thus, the PGE(2)-EP3 pathway is an important negative modulator of allergic reactions...

..PGE2-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells...

..This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease...

..These results indicate that the protection of atherogenesis in TP(-/-) mice is not associated with TP in BM-derived cells...

..Host EP3 blockade together with COX-2 inhibition may be a novel therapeutic strategy to suppress tumor-associated lymphangiogenesis...

..These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF...

..Consistently, ROCK-I(+/-)ROCK-II(+/-) double heterozygous mice also show the EOB and omphalocele phenotype...

..Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses...

..These data suggest that PGE(2)-EP2/EP4 signaling is mandatory in UV-induced acute skin inflammation, presumably by enhancing blood flow in the microenvironment...

..An EP3 receptor antagonist may be useful to protect against tumor metastasis...

..These results suggest that ROCK-I regulates closure of the eyelids and ventral body wall through organization of actomyosin bundles...

..These results suggest that mDia2 continuously shuttles between the nucleus and the cytoplasm using specific nuclear transport machinery composing of importin-alpha/beta and CRM1...

..Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms...

..The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction...

..We now show that one member of this family, Cdc42, and its effector, mDia3, regulate MT attachment to kinetochores...

..These results demonstrate that mDia2 is essential in mammalian cell cytokinesis and that mDia2-induced F-actin forms a scaffold for the contractile ring and maintains its position in the middle of a dividing cell...

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..These results suggest that PGI(2)-IP signaling promotes Th1 differentiation through a cAMP-protein kinase A pathway and thereby initiates acquired cutaneous immune responses...

..Furthermore, RNAi knockdown of mDia1 abolished SDF-1alpha-induced axon elongation. Together, our results support a critical role for an SDF-1alpha/Rho/mDia1 pathway in mediating axon elongation...

..Although EP(3) is also expressed in skin and PGE(2) is produced abundantly during skin allergic inflammation, the role of PGE(2)-EP(3) signaling in skin allergic inflammation remains unknown...

..Thus, the Rho-mDia1 pathway regulates polarization and adhesion turnover by aligning microtubules and actin filaments and delivering Apc/Cdc42 and c-Src to their respective sites of action...

..These findings suggest that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness...

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..The present study suggests that the blockade of EP3 signaling and the recruitment of EP3-expressing stromal cells may become a novel strategy to treat solid tumors...

..Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases...

..These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors...

..Similarly, mDia1(-/-) thymocytes showed reduced chemotaxis and impaired egression from the thymus. These results suggest that mDia1 plays a distinct role in chemotaxis in T lymphocyte trafficking...

..These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF...

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..These data suggest that TP stimulation in the striatum locally facilitates dopamine overflow evoked by synaptic inputs via NO synthesis in endothelial cells...

..These results suggest that prostaglandin E(2) acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans...

..These results suggest that Rho GTPases are activated at specific points in mitosis and regulate each step. Here we describe the methods to analyze the activity and regulation of Rho GTPases during mitosis...

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..Although such roles of PGs should be verified in human diseases, these findings suggest that PG signaling is a promising therapeutic target of chronic inflammatory diseases...

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..Similar immune responses were seen in wild-type mice treated with a TP antagonist during the sensitization period. Thus, TXA2-TP signaling modulates acquired immunity by negatively regulating DC-T cell interactions...

..We previously demonstrated that the prostaglandin E(2) (PGE(2))-EP3 pathway negatively regulates allergic reactions in a murine allergic asthma model...

..Therefore, the prostaglandin E(2)-EP1 signaling directly enhances GABAergic inputs to SNc dopaminergic neurons. The lack of this EP1 action may lead to a hyperdopaminergic state of EP1-deficient mice...

..CONCLUSIONS: These results suggest that TXA2 has a protective role against the development of vascular hyporesponsiveness via its inhibitory action on the iNOS-NO system under pathological conditions such as sepsis...

..We predict that filament severing and end-to-end annealing might take place fairly frequently in the dendritic nucleation actin arrays...

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..Taken together, we propose that transient accumulation of G-actin works as a cue to promote mDia1-catalyzed actin nucleation to execute rapid reassembly of actin filaments...

..These results demonstrate participation of EP2 and EP3 along with IP in pleural exudate formation but not in leukocyte migration in carrageenin-induced mouse pleurisy...

..We evaluated whether prostaglandin I(2) plays a role in the regulation of the function of EPCs to limit vascular remodeling...

..Roles of prostanoids in the generation of inflammatory tachycardia and the regulation of platelet function have also been clarified. In this review, we summarize these roles of prostanoids revealed from knockout mouse studies...

..Based on these results, we propose that prostaglandin E(2)-EP2 signaling negatively regulates chemokine-induced Rho/ROCK signaling in cumulus cells for successful fertilization...

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..These findings suggest a regulatory role of PGI(2) in allergic inflammation...

..In addition, EP1 controls impulsive behaviors under psychological stress through the dopaminergic system. PGE(2) produced by various cell types may integrate multiple stress stimuli through PGE receptor subtypes for adaptive responses...

..Here, we review the findings obtained in these studies. The results from these knockout mice studies may be useful in the development of novel therapeutics that can selectively manipulate actions mediated by each receptor...

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..These findings shed a new light on the roles of prostanoids in T cell-mediated immunity and immune diseases...

..Dependent on the type of stress stimuli, PGE(2) released from different cell types activates distinct EP receptors, which mobilize multiple neuronal pathways, resulting in stress responses...

..We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response...

..These novel findings on the roles of the prostanoids would contribute to the development of drugs targeting the prostanoid receptors...

..Here we review recent advances in PGE receptor research...

..Recently, we have found a mitosis-specific role of Cdc42 by enrichment of cells in mitosis by cell cycle synchronization and interfering with functions of Rho GTPases. This chapter describes the procedures we used in these studies...

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..These results suggest that PGE2 is formed in response to dopamine receptor stimulation in the striatum and amplifies both D1 and D2 receptor signaling via EP1...

..In this article, we summarize these findings and provide an overview of the current status of the DP receptor research to discuss the therapeutic potential of modulating the PGD(2)-DP pathway in allergic diseases...

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..This interaction between PG and chemokine signaling is required for successful fertilization...

..This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease...

..Thus, these results have revealed the Rho-dependent Rac activation signaling that is mediated by mDia1 through Cas phosphorylation and antagonized by the action of ROCK...

..These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis...

..Taken together, we propose that Rhotekin is a novel regulator organizing mammalian septin structures and provide a new link between the septin and Rho-signaling...

..Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition...

..Our results thus provide further evidence that inflammatory hyperalgesia and neuropathic pain involve different mechanisms of central sensitization...

..Ultimately, these pathways converge in the nucleus to regulate AP1 activity...

..mDia1 probably moves processively along the growing end of actin filaments in cells, and Formins may be a molecular motility machinery that is independent from motor proteins...

..It was further confirmed that the PG systems do not play a key role in delayed postherpetic pain...

..In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model...

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..In conclusion, inhibition of ROCK-II, not ROCK-I, enhances adipogenesis accompanied by the up-regulation of adipogenic transcription factors. Augmentation of insulin signaling may contribute to the enhancement of adipogenesis...

..These results suggest that gp120 induced allodynia by increasing [Ca2+]i, concomitant with activation of prostanoid EP3 and kappa-opioid receptors in the spinal cord...