The Experts below are selected from a list of 117684 Experts worldwide ranked by ideXlab platform
Alan B Frey - One of the best experts on this subject based on the ideXlab platform.
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defective proximal tcr signaling inhibits cd8 tumor infiltrating lymphocyte lytic function
Journal of Immunology, 2005Co-Authors: Mythili Koneru, David Schaer, Ngozi Monu, Aidee Ayala, Alan B FreyAbstract:CD8 + tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL Proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B + granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome Protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56 lck , CD3ζ, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56 lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing Protein Phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
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defective proximal tcr signaling inhibits cd8 tumor infiltrating lymphocyte lytic function
Journal of Immunology, 2005Co-Authors: Mythili Koneru, David Schaer, Ngozi Monu, Aidee Ayala, Alan B FreyAbstract:CD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL Proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome Protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3zeta, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing Protein Phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
Soo Young Park - One of the best experts on this subject based on the ideXlab platform.
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15d pgj2 and rosiglitazone suppress janus kinase stat inflammatory signaling through induction of suppressor of cytokine signaling 1 socs1 and socs3 in glia
Journal of Biological Chemistry, 2003Co-Authors: Eun Jung Park, Soo Young ParkAbstract:Abstract Peroxisome proliferator-activated receptor (PPAR)-γ agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-γ agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-γ agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ2 and rosiglitazone are not mediated by activation of PPAR-γ. 15d-PGJ2 and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing Protein Phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ2 and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-γ, thus attenuating brain inflammation.
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15d pgj2 and rosiglitazone suppress janus kinase stat inflammatory signaling through induction of suppressor of cytokine signaling 1 socs1 and socs3 in glia
Journal of Biological Chemistry, 2003Co-Authors: Eun Jung Park, Soo Young Park, Eunhye Joe, Ilo JouAbstract:Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-gamma agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-gamma agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ(2) and rosiglitazone are not mediated by activation of PPAR-gamma. 15d-PGJ(2) and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing Protein Phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ(2) and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-gamma, thus attenuating brain inflammation.
Mythili Koneru - One of the best experts on this subject based on the ideXlab platform.
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defective proximal tcr signaling inhibits cd8 tumor infiltrating lymphocyte lytic function
Journal of Immunology, 2005Co-Authors: Mythili Koneru, David Schaer, Ngozi Monu, Aidee Ayala, Alan B FreyAbstract:CD8 + tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL Proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B + granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome Protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56 lck , CD3ζ, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56 lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing Protein Phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
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defective proximal tcr signaling inhibits cd8 tumor infiltrating lymphocyte lytic function
Journal of Immunology, 2005Co-Authors: Mythili Koneru, David Schaer, Ngozi Monu, Aidee Ayala, Alan B FreyAbstract:CD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL Proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome Protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3zeta, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing Protein Phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
Eun Jung Park - One of the best experts on this subject based on the ideXlab platform.
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15d pgj2 and rosiglitazone suppress janus kinase stat inflammatory signaling through induction of suppressor of cytokine signaling 1 socs1 and socs3 in glia
Journal of Biological Chemistry, 2003Co-Authors: Eun Jung Park, Soo Young ParkAbstract:Abstract Peroxisome proliferator-activated receptor (PPAR)-γ agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-γ agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-γ agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ2 and rosiglitazone are not mediated by activation of PPAR-γ. 15d-PGJ2 and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing Protein Phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ2 and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-γ, thus attenuating brain inflammation.
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15d pgj2 and rosiglitazone suppress janus kinase stat inflammatory signaling through induction of suppressor of cytokine signaling 1 socs1 and socs3 in glia
Journal of Biological Chemistry, 2003Co-Authors: Eun Jung Park, Soo Young Park, Eunhye Joe, Ilo JouAbstract:Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-gamma agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-gamma agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ(2) and rosiglitazone are not mediated by activation of PPAR-gamma. 15d-PGJ(2) and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing Protein Phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ(2) and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-gamma, thus attenuating brain inflammation.
Matthew K Topham - One of the best experts on this subject based on the ideXlab platform.
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diacylglycerol kinase δ modulates akt phosphorylation through pleckstrin homology domain leucine rich repeat Protein Phosphatase 2 phlpp2
Journal of Biological Chemistry, 2013Co-Authors: Tracy Crotty, Tomoyuki Nakano, Diana M Stafforini, Matthew K TophamAbstract:Discovering Proteins that modulate Akt signaling has become a critical task, given the oncogenic role of Akt in a wide variety of cancers. We have discovered a novel diacylglycerol signaling pathway that promotes dephosphorylation of Akt. This pathway is regulated by diacylglycerol kinase δ (DGKδ). In DGKδ-deficient cells, we found reduced Akt phosphorylation downstream of three receptor tyrosine kinases. Phosphorylation upstream of Akt was not affected. Our data indicate that PKCα, which is excessively active in DGKδ-deficient cells, promotes dephosphorylation of Akt through pleckstrin homology domain leucine-rich repeats Protein Phosphatase (PHLPP) 2. Depletion of either PKCα or PHLPP2 rescued Akt phosphorylation in DGKδ-deficient cells. In contrast, depletion of PHLPP1, another Akt Phosphatase, failed to rescue Akt phosphorylation. Other PHLPP substrates were not affected by DGKδ deficiency, suggesting mechanisms allowing specific modulation of Akt dephosphorylation. We found that β-arrestin 1 acted as a scaffold for PHLPP2 and Akt1, providing a mechanism for specificity. Because of its ability to reduce Akt phosphorylation, we tested whether depletion of DGKδ could attenuate tumorigenic properties of cultured cells and found that DGKδ deficiency reduced cell proliferation and migration and enhanced apoptosis. We have, thus, discovered a novel pathway in which diacylglycerol signaling negatively regulates Akt activity. Our collective data indicate that DGKδ is a pertinent cancer target, and our studies could lay the groundwork for development of novel cancer therapeutics.
