The Experts below are selected from a list of 18 Experts worldwide ranked by ideXlab platform
Charles Eigenbrot - One of the best experts on this subject based on the ideXlab platform.
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structure of the pseudoKinase Kinase domains from Protein Kinase TYK2 reveals a mechanism for janus Kinase jak autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
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Structure of the pseudoKinase–Kinase domains from Protein Kinase TYK2 reveals a mechanism for Janus Kinase (JAK) autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
James N. Ihle - One of the best experts on this subject based on the ideXlab platform.
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Complementation by the Protein tyrosine Kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway
Nature, 1993Co-Authors: Diane Watling, Dmitry Guschin, Mathias Müller, Olli Silvennoinen, Bruce A. Witthuhn, Frederick W. Quelle, Neil C. Rogers, Chris Schindler, George R. Stark, James N. IhleAbstract:I NTERFERONS (IFNs) & alpha;/& beta; (type I) and & gamma; (type II) bind to distinct cell surface receptors^1, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention^2,3. Previous studies using cell lines selected for their inability to respond to IFN-& alpha; (ref. 4) have shown that the Protein Kinase TYK2 plays a central role in the IFN & alpha;/& beta; response^5. Here we report the isolation of the cell line & gamma;l A, selected for its inability to express IFN-& gamma;-inducible cell-surface markers, that is deficient in all aspects of the IFN-& gamma; response tested, but responds normally to IFNs & alpha; and & beta;. The mutant cells can be complemented by the expression of another member of the JAK family of Protein tyro-sine Kinases, JAK2 (refs 6& ndash;9). Unlike IFNs & alpha; and & beta;, IFN-& gamma; induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine Kinase activity. These responses are absent in & gamma;l A cells. JAK2 is therefore required for the response to IFN-& gamma; but not to IFNs & alpha; and & beta;.
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Complementation by the Protein tyrosine Kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway
Nature, 1993Co-Authors: Diane Watling, Dmitry Guschin, Mathias Müller, Olli Silvennoinen, Bruce A. Witthuhn, Frederick W. Quelle, Neil C. Rogers, Chris Schindler, George R. Stark, James N. IhleAbstract:INTERFERONS (IFNs) & alpha;/& beta; (type I) and & gamma; (type II) bind to distinct cell surface receptors1, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention2,3. Previous studies using cell lines selected for their inability to respond to IFN-& alpha; (ref. 4) have shown that the Protein Kinase TYK2 plays a central role in the IFN & alpha;/& beta; response5. Here we report the isolation of the cell line & gamma;l A, selected for its inability to express IFN-& gamma;-inducible cell-surface markers, that is deficient in all aspects of the IFN-& gamma; response tested, but responds normally to IFNs & alpha; and & beta;. The mutant cells can be complemented by the expression of another member of the JAK family of Protein tyro-sine Kinases, JAK2 (refs 6& ndash;9). Unlike IFNs & alpha; and & beta;, IFN-& gamma; induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine Kinase activity. These responses are absent in & gamma;l A cells. JAK2 is therefore required for the response to IFN-& gamma; but not to IFNs & alpha; and & beta;.
Patrick J. Lupardus - One of the best experts on this subject based on the ideXlab platform.
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structure of the pseudoKinase Kinase domains from Protein Kinase TYK2 reveals a mechanism for janus Kinase jak autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
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Structure of the pseudoKinase–Kinase domains from Protein Kinase TYK2 reveals a mechanism for Janus Kinase (JAK) autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
Diane Watling - One of the best experts on this subject based on the ideXlab platform.
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Complementation by the Protein tyrosine Kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway
Nature, 1993Co-Authors: Diane Watling, Dmitry Guschin, Mathias Müller, Olli Silvennoinen, Bruce A. Witthuhn, Frederick W. Quelle, Neil C. Rogers, Chris Schindler, George R. Stark, James N. IhleAbstract:I NTERFERONS (IFNs) & alpha;/& beta; (type I) and & gamma; (type II) bind to distinct cell surface receptors^1, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention^2,3. Previous studies using cell lines selected for their inability to respond to IFN-& alpha; (ref. 4) have shown that the Protein Kinase TYK2 plays a central role in the IFN & alpha;/& beta; response^5. Here we report the isolation of the cell line & gamma;l A, selected for its inability to express IFN-& gamma;-inducible cell-surface markers, that is deficient in all aspects of the IFN-& gamma; response tested, but responds normally to IFNs & alpha; and & beta;. The mutant cells can be complemented by the expression of another member of the JAK family of Protein tyro-sine Kinases, JAK2 (refs 6& ndash;9). Unlike IFNs & alpha; and & beta;, IFN-& gamma; induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine Kinase activity. These responses are absent in & gamma;l A cells. JAK2 is therefore required for the response to IFN-& gamma; but not to IFNs & alpha; and & beta;.
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Complementation by the Protein tyrosine Kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway
Nature, 1993Co-Authors: Diane Watling, Dmitry Guschin, Mathias Müller, Olli Silvennoinen, Bruce A. Witthuhn, Frederick W. Quelle, Neil C. Rogers, Chris Schindler, George R. Stark, James N. IhleAbstract:INTERFERONS (IFNs) & alpha;/& beta; (type I) and & gamma; (type II) bind to distinct cell surface receptors1, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention2,3. Previous studies using cell lines selected for their inability to respond to IFN-& alpha; (ref. 4) have shown that the Protein Kinase TYK2 plays a central role in the IFN & alpha;/& beta; response5. Here we report the isolation of the cell line & gamma;l A, selected for its inability to express IFN-& gamma;-inducible cell-surface markers, that is deficient in all aspects of the IFN-& gamma; response tested, but responds normally to IFNs & alpha; and & beta;. The mutant cells can be complemented by the expression of another member of the JAK family of Protein tyro-sine Kinases, JAK2 (refs 6& ndash;9). Unlike IFNs & alpha; and & beta;, IFN-& gamma; induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine Kinase activity. These responses are absent in & gamma;l A cells. JAK2 is therefore required for the response to IFN-& gamma; but not to IFNs & alpha; and & beta;.
Pawan Bir Kohli - One of the best experts on this subject based on the ideXlab platform.
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structure of the pseudoKinase Kinase domains from Protein Kinase TYK2 reveals a mechanism for janus Kinase jak autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
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Structure of the pseudoKinase–Kinase domains from Protein Kinase TYK2 reveals a mechanism for Janus Kinase (JAK) autoinhibition
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Patrick J. Lupardus, Mark Ultsch, Heidi J.a. Wallweber, Pawan Bir Kohli, Adam R. Johnson, Charles EigenbrotAbstract:Janus Kinases (JAKs) are receptor-associated multidomain tyrosine Kinases that act downstream of many cytokines and interferons. JAK Kinase activity is regulated by the adjacent pseudoKinase domain via an unknown mechanism. Here, we report the 2.8-A structure of the two-domain pseudoKinase–Kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudoKinase and Kinase interact near the Kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and “exon 12” JAK2 mutations, results in increased Kinase activity in vitro. These data indicate that JAK pseudoKinases are autoinhibitory domains that hold the Kinase domain inactive until receptor dimerization stimulates transition to an active state.
