Browsing by Subject "p21-Activated Kinases"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3 and KIT driven Leukemogenesis
    (Elsevier B.V., 2014-11-20) Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H.; Waskow, Emily R.; Visconte, Valeria; Tiu, Ramon V.; Smith, Catherine C.; Shah, Neil; Bunting, Kevin D.; Boswell, H. Scott; Liu, Yan; Chan, Rebecca J.; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.
  • Thumbnail Image
    Item
    Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase
    (Nature Publishing Group, 2014-11) Molosh, Andrei I.; Johnson, Philip L.; Spence, John P.; Arendt, David; Federici, Lauren M.; Bernabe, Cristian; Janasik, Steven P.; Segu, Zaneer M.; Khanna, Rajesh; Goswami, Chirayu; Zhu, Weiguo; Park, Su-Jung; Li, Lang; Mechref, Yehia S.; Clapp, D. Wade; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1+/−), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate/GABA neurotransmission