23 research outputs found
A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells
BACKGROUND: Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-Ī³2 (PLCĪ³2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCĪ³2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCĪ³2-deficient DT40 B cell line. RESULTS: Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCĪ³2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCĪ³2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, and apoptosis. In DT40 B cells deficient for PLCĪ³2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. CONCLUSIONS: These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCĪ³2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types
Role of Tyrosine Phosphorylation in Radiation-Induced Cell Cycle-Arrest of Leukemic B-Cell Precursors at the G2-M Transition Checkpoint
Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies
MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors
The
Aurora kinases are essential for cell mitosis, and the dysregulation
of Aurora A and B have been linked to the etiology of human cancers.
Investigational agents MLN8054 (<b>8</b>) and alisertib (MLN8237, <b>10</b>) have been identified as high affinity, selective, orally
bioavailable inhibitors of Aurora A that have advanced into human
clinical trials. Alisertib (<b>10</b>) is currently being evaluated
in multiple Phase II and III clinical trials in hematological malignancies
and solid tumors