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Stefan Offermanns - One of the best experts on this subject based on the ideXlab platform.
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G12 g13 mediated signalling in mammalian physiology and disease
Trends in Pharmacological Sciences, 2008Co-Authors: Thomas Worzfeld, Stefan Offermanns, Nina WettschureckAbstract:The human genome encodes hundreds of G-protein-coupled receptors. Their intracellular effects, however, are mediated by only four families of heterotrimeric G proteins: G s , G i /G o , G q /G 11 and G 12 /G 13 . Progress in the knowledge about the G 12 /G 13 family has somewhat lagged behind because their downstream effectors remained unknown for several years, and tools to specifically interfere with G 12 /G 13 -mediated signalling were, therefore, missing. However, with the identification of G 12 /G 13 -regulated signalling pathways and the recent application of new techniques, such as conditional gene inactivation, RNA interference or expression of inhibitory proteins, new insights into the in vivo functions of this G-protein family have been gained. It has become clear that this pathway regulates cellular proliferation, movement and morphology in many different organs and that it is centrally involved in various diseases including cancer and cardiovascular disorders. Here, we focus on recent progress made in the analyses of the in vivo functions of mammalian G 12 /G 13 -mediated signalling.
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role for G12 g13 in agonist induced vascular smooth muscle cell contraction
Circulation Research, 2000Co-Authors: Antje Gohla, Gunter Schultz, Stefan OffermannsAbstract:Abstract —Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC20) phosphorylation through Ca2+-dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the Gq family, Gq and G11, it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to Gq/G11 and G12/G13, and constitutively active forms of Gα12 and Gα13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative forms of Gα12 and Gα13. These data indicate that a G12/G13-mediated Rho/Rho-kinase–dependent pathway operates in smooth muscle cells and that dual regulation of MLC20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the Gq and G12 families.
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activation of G12 g13 results in shape change and rho rho kinase mediated myosin light chain phosphorylation in mouse platelets
Journal of Cell Biology, 1999Co-Authors: Birgit Klages, Gunter Schultz, Ursula Brandt, Melvin I Simon, Stefan OffermannsAbstract:Platelets respond to various stimuli with rapid changes in shape followed by aggregation and secretion of their granule contents. Platelets lacking the α-subunit of the heterotrimeric G protein Gq do not aggregate and degranulate but still undergo shape change after activation through thromboxane-A2 (TXA2) or thrombin receptors. In contrast to thrombin, the TXA2 mimetic U46619 led to the selective activation of G12 and G13 in Gαq-deficient platelets indicating that these G proteins mediate TXA2 receptor-induced shape change. TXA2 receptor-mediated activation of G12/G13 resulted in tyrosine phosphorylation of pp72syk and stimulation of pp60c-src as well as in phosphorylation of myosin light chain (MLC) in Gαq-deficient platelets. Both MLC phosphorylation and shape change induced through G12/G13 in the absence of Gαq were inhibited by the C3 exoenzyme from Clostridium botulinum , by the Rho-kinase inhibitor Y-27632 and by cAMP-analogue Sp-5,6-DCl-cBIMPS. These data indicate that G12/G13 couple receptors to tyrosine kinases as well as to the Rho/Rho-kinase–mediated regulation of MLC phosphorylation. We provide evidence that G12/G13-mediated Rho/Rho-kinase–dependent regulation of MLC phosphorylation participates in receptor-induced platelet shape change.
Gunter Schultz - One of the best experts on this subject based on the ideXlab platform.
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role for G12 g13 in agonist induced vascular smooth muscle cell contraction
Circulation Research, 2000Co-Authors: Antje Gohla, Gunter Schultz, Stefan OffermannsAbstract:Abstract —Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC20) phosphorylation through Ca2+-dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the Gq family, Gq and G11, it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to Gq/G11 and G12/G13, and constitutively active forms of Gα12 and Gα13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative forms of Gα12 and Gα13. These data indicate that a G12/G13-mediated Rho/Rho-kinase–dependent pathway operates in smooth muscle cells and that dual regulation of MLC20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the Gq and G12 families.
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activation of G12 g13 results in shape change and rho rho kinase mediated myosin light chain phosphorylation in mouse platelets
Journal of Cell Biology, 1999Co-Authors: Birgit Klages, Gunter Schultz, Ursula Brandt, Melvin I Simon, Stefan OffermannsAbstract:Platelets respond to various stimuli with rapid changes in shape followed by aggregation and secretion of their granule contents. Platelets lacking the α-subunit of the heterotrimeric G protein Gq do not aggregate and degranulate but still undergo shape change after activation through thromboxane-A2 (TXA2) or thrombin receptors. In contrast to thrombin, the TXA2 mimetic U46619 led to the selective activation of G12 and G13 in Gαq-deficient platelets indicating that these G proteins mediate TXA2 receptor-induced shape change. TXA2 receptor-mediated activation of G12/G13 resulted in tyrosine phosphorylation of pp72syk and stimulation of pp60c-src as well as in phosphorylation of myosin light chain (MLC) in Gαq-deficient platelets. Both MLC phosphorylation and shape change induced through G12/G13 in the absence of Gαq were inhibited by the C3 exoenzyme from Clostridium botulinum , by the Rho-kinase inhibitor Y-27632 and by cAMP-analogue Sp-5,6-DCl-cBIMPS. These data indicate that G12/G13 couple receptors to tyrosine kinases as well as to the Rho/Rho-kinase–mediated regulation of MLC phosphorylation. We provide evidence that G12/G13-mediated Rho/Rho-kinase–dependent regulation of MLC phosphorylation participates in receptor-induced platelet shape change.
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the g protein g13 but not G12 mediates signaling from lysophosphatidic acid receptor via epidermal growth factor receptor to rho
Journal of Biological Chemistry, 1998Co-Authors: Antje Gohla, Rainer Harhammer, Gunter SchultzAbstract:Abstract Lysophosphatidic acid (LPA) utilizes a G-protein-coupled receptor to activate the small GTP-binding protein Rho and to induce rapid remodeling of the actin cytoskeleton. We studied the signal transduction from LPA receptors to Rho activation. Analysis of the G-protein-coupling pattern of LPA receptors by labeling activated G-proteins with [α-32P]GTP azidoanilide revealed interaction with proteins of the Gq, Gi, and G12 subfamilies. We could show that in COS-7 cells, expression of GTPase-deficient mutants of Gα12 and Gα13 triggered Rho activation as measured by increased Rho-GTP levels. In Swiss 3T3 cells, incubation with LPA or microinjection of constitutively active mutants of Gα12 and Gα13 induced formation of actin stress fibers and assembly of focal adhesions in a Rho-dependent manner. Interestingly, the LPA-dependent cytoskeletal reorganization was suppressed by microinjected antibodies directed against Gα13, whereas Gα12-specific antibodies showed no inhibition. The tyrosine kinase inhibitor tyrphostin A 25 and the epidermal growth factor (EGF) receptor-specific tyrphostin AG 1478 completely blocked actin stress fiber formation caused by LPA or activated Gα13 but not the effects of activated Gα12. Also, expression of the dominant negative EGF receptor mutant EGFR-CD533 markedly prevented the LPA- and Gα13-induced actin polymerization. Coexpression of EGFR-CD533 and activated Gα13 in COS-7 cells resulted in decreased Rho-GTP levels compared with expression of activated Gα13 alone. These data indicate that in Swiss 3T3 cells, G13 but not G12 is involved in the LPA-induced activation of Rho. Moreover, our results suggest an involvement of the EGF receptor in this pathway.
Hany Ariffin - One of the best experts on this subject based on the ideXlab platform.
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transcriptional landscape of b cell precursor acute lymphoblastic leukemia based on an international study of 1 223 cases
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Jianfeng Li, Henrik Lilljebjorn, Shu Hong Shen, Mao Xiang Qian, Yasuo Kubota, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Linda Olsson, Hany AriffinAbstract:Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
Antje Gohla - One of the best experts on this subject based on the ideXlab platform.
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role for G12 g13 in agonist induced vascular smooth muscle cell contraction
Circulation Research, 2000Co-Authors: Antje Gohla, Gunter Schultz, Stefan OffermannsAbstract:Abstract —Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC20) phosphorylation through Ca2+-dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the Gq family, Gq and G11, it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to Gq/G11 and G12/G13, and constitutively active forms of Gα12 and Gα13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative forms of Gα12 and Gα13. These data indicate that a G12/G13-mediated Rho/Rho-kinase–dependent pathway operates in smooth muscle cells and that dual regulation of MLC20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the Gq and G12 families.
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the g protein g13 but not G12 mediates signaling from lysophosphatidic acid receptor via epidermal growth factor receptor to rho
Journal of Biological Chemistry, 1998Co-Authors: Antje Gohla, Rainer Harhammer, Gunter SchultzAbstract:Abstract Lysophosphatidic acid (LPA) utilizes a G-protein-coupled receptor to activate the small GTP-binding protein Rho and to induce rapid remodeling of the actin cytoskeleton. We studied the signal transduction from LPA receptors to Rho activation. Analysis of the G-protein-coupling pattern of LPA receptors by labeling activated G-proteins with [α-32P]GTP azidoanilide revealed interaction with proteins of the Gq, Gi, and G12 subfamilies. We could show that in COS-7 cells, expression of GTPase-deficient mutants of Gα12 and Gα13 triggered Rho activation as measured by increased Rho-GTP levels. In Swiss 3T3 cells, incubation with LPA or microinjection of constitutively active mutants of Gα12 and Gα13 induced formation of actin stress fibers and assembly of focal adhesions in a Rho-dependent manner. Interestingly, the LPA-dependent cytoskeletal reorganization was suppressed by microinjected antibodies directed against Gα13, whereas Gα12-specific antibodies showed no inhibition. The tyrosine kinase inhibitor tyrphostin A 25 and the epidermal growth factor (EGF) receptor-specific tyrphostin AG 1478 completely blocked actin stress fiber formation caused by LPA or activated Gα13 but not the effects of activated Gα12. Also, expression of the dominant negative EGF receptor mutant EGFR-CD533 markedly prevented the LPA- and Gα13-induced actin polymerization. Coexpression of EGFR-CD533 and activated Gα13 in COS-7 cells resulted in decreased Rho-GTP levels compared with expression of activated Gα13 alone. These data indicate that in Swiss 3T3 cells, G13 but not G12 is involved in the LPA-induced activation of Rho. Moreover, our results suggest an involvement of the EGF receptor in this pathway.
Tasnim Azim - One of the best experts on this subject based on the ideXlab platform.
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reassortment of human rotavirus gene segments into g11 rotavirus strains
Emerging Infectious Diseases, 2010Co-Authors: Jelle Matthijnssens, Tasnim Azim, Toyoko Nakagomi, Ryuichi Uchida, Mustafizur Rahman, Max Ciarlet, Mark Zeller, Elisabeth Heylen, Zahid Hassan, Osamu NakagomiAbstract:G11 rotaviruses are believed to be of porcine origin. However, a limited number of G11 rotaviruses have been recently isolated from humans in combination with P[25], P[8], P[6], and P[4]. To investigate the evolutionary relationships of these strains, we analyzed the complete genomes of 2 human G11P[25] strains, 2 human G11P[8] strains, and 3 porcine reference strains. Most of the 11 gene segments of these 7 strains belonged to genotype 1 (Wa-like). However, phylogenetic clustering patterns suggested that an unknown G11P[25] strain with a new I12 VP6 genotype was transmitted to the human population, in which it acquired human genotype 1 gene segments through reassortment, resulting in a human G11P[8] rotavirus strain with an entire human Wa-genogroup backbone. This Wa-like backbone is believed to have caused the worldwide spread of human G9 and G12 rotaviruses. G11 human rotavirus strains should be monitored because they may also become major human pathogens.
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evolutionary history and global spread of the emerging G12 human rotaviruses
Journal of Virology, 2007Co-Authors: Jelle Matthijnssens, Thomas Delbeke, Xuelei Yang, Miren Iturrizagomara, N Iftekharuddin, Ingrid Arijs, Koki Taniguchi, Tasnim AzimAbstract:G12 rotaviruses were first detected in diarrheic children in the Philippines in 1987, but no further cases were reported until 1998. However, G12 rotaviruses have been detected all over the world in recent years. Here, we report the worldwide variations of G12 rotaviruses to investigate the evolutionary mechanisms by which they managed to spread globally in a short period of time. We sequenced the complete genomes (11 segments) of nine G12 rotaviruses isolated in Bangladesh, Belgium, Thailand, and the Philippines and compared them with the genomes of other rotavirus strains. Our genetic analyses revealed that after introduction of the VP7 gene of the rare G12 genotype into more common local strains through reassortment, a vast genetic diversity was generated and several new variants with distinct gene constellations emerged. These reassortment events most likely took place in Southeast Asian countries and spread to other parts of the world. The acquirement of gene segments from human-adapted rotaviruses might allow G12 to better propagate in humans and hence to develop into an important emerging human pathogen.
