The Experts below are selected from a list of 12435 Experts worldwide ranked by ideXlab platform

Naila Chughtai - One of the best experts on this subject based on the ideXlab platform.

  • shp 2 regulates socs 1 mediated Janus Kinase 2 ubiquitination degradation downstream of the prolactin receptor
    Journal of Biological Chemistry, 2003
    Co-Authors: Zaynab Nouhi, Naila Chughtai
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.

  • SHP-2 Regulates SOCS-1-mediated Janus Kinase-2 Ubiquitination/Degradation Downstream of the Prolactin Receptor
    The Journal of biological chemistry, 2003
    Co-Authors: Samir Ali, Zaynab Nouhi, Naila Chughtai, Suhad Ali
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.

Zaynab Nouhi - One of the best experts on this subject based on the ideXlab platform.

  • shp 2 regulates socs 1 mediated Janus Kinase 2 ubiquitination degradation downstream of the prolactin receptor
    Journal of Biological Chemistry, 2003
    Co-Authors: Zaynab Nouhi, Naila Chughtai
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.

  • SHP-2 Regulates SOCS-1-mediated Janus Kinase-2 Ubiquitination/Degradation Downstream of the Prolactin Receptor
    The Journal of biological chemistry, 2003
    Co-Authors: Samir Ali, Zaynab Nouhi, Naila Chughtai, Suhad Ali
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.

Suhad Ali - One of the best experts on this subject based on the ideXlab platform.

  • SHP-2 Regulates SOCS-1-mediated Janus Kinase-2 Ubiquitination/Degradation Downstream of the Prolactin Receptor
    The Journal of biological chemistry, 2003
    Co-Authors: Samir Ali, Zaynab Nouhi, Naila Chughtai, Suhad Ali
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.

Srdan Verstovsek - One of the best experts on this subject based on the ideXlab platform.

  • Comprehensive Kinase profile of pacritinib, a nonmyelosuppressive Janus Kinase 2 inhibitor
    Journal of experimental pharmacology, 2016
    Co-Authors: Jack W. Singer, Suliman Al-fayoumi, Rami S. Komrokji, Ruben A. Mesa, Srdan Verstovsek
    Abstract:

    Pacritinib, potent inhibitor of Janus Kinase 2 (JAK2), JAK2V617F, and fms-like receptor tyrosine Kinase 3, is in Phase III development in myelofibrosis. Among type 1 inhibitors, pacritinib shows a lack of myelosuppression at doses that both inhibit JAK2/signal transducer and activator of transcription 3 pathway and demonstrate clinical efficacy. To elucidate these mechanisms and identify other disease targets, a kinome analysis screened 439 recombinant Kinases at 100 nM pacritinib concentration. For Kinases with >50% inhibition, pacritinib was titrated from 1 to 100 nM. JAK2, JAK2V617F, FLT3, colony-stimulating factor 1 receptor, and interleukin-1 receptor-associated Kinase 1 achieved half-maximal inhibitory concentrations

  • comprehensive Kinase profile of pacritinib a nonmyelosuppressive Janus Kinase 2 inhibitor
    Journal of experimental pharmacology, 2016
    Co-Authors: Jack W. Singer, Rami S. Komrokji, Ruben A. Mesa, Suliman Alfayoumi, Srdan Verstovsek
    Abstract:

    Pacritinib, potent inhibitor of Janus Kinase 2 (JAK2), JAK2V617F, and fms-like receptor tyrosine Kinase 3, is in Phase III development in myelofibrosis. Among type 1 inhibitors, pacritinib shows a lack of myelosuppression at doses that both inhibit JAK2/signal transducer and activator of transcription 3 pathway and demonstrate clinical efficacy. To elucidate these mechanisms and identify other disease targets, a kinome analysis screened 439 recombinant Kinases at 100 nM pacritinib concentration. For Kinases with >50% inhibition, pacritinib was titrated from 1 to 100 nM. JAK2, JAK2V617F, FLT3, colony-stimulating factor 1 receptor, and interleukin-1 receptor-associated Kinase 1 achieved half-maximal inhibitory concentrations <50 nM. Pacritinib did not inhibit JAK1 (82% control at 100 nM). Lack of myelosuppression may stem from inhibiting JAK2 without affecting JAK1 and reducing hematopoietic inhibitory cytokines by suppressing interleukin-1 receptor-associated Kinase 1 or colony-stimulating factor 1 receptor. The pacritinib kinome suggests therapeutic utility in acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, solid tumors, and inflammatory conditions.

  • Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus Kinase 2 inhibitors
    Journal of hematology & oncology, 2012
    Co-Authors: Jasleen K Randhawa, Alen Ostojić, Radovan Vrhovac, Ehab Atallah, Srdan Verstovsek
    Abstract:

    Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus Kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

  • splenomegaly in myelofibrosis new options for therapy and the therapeutic potential of Janus Kinase 2 inhibitors
    Journal of Hematology & Oncology, 2012
    Co-Authors: Jasleen K Randhawa, Radovan Vrhovac, Ehab Atallah, Alen Ostojic, Srdan Verstovsek
    Abstract:

    Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus Kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

Samir Ali - One of the best experts on this subject based on the ideXlab platform.

  • SHP-2 Regulates SOCS-1-mediated Janus Kinase-2 Ubiquitination/Degradation Downstream of the Prolactin Receptor
    The Journal of biological chemistry, 2003
    Co-Authors: Samir Ali, Zaynab Nouhi, Naila Chughtai, Suhad Ali
    Abstract:

    Abstract The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus Kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 Kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.