RRC ID 65687
Author Doi K, Imai T, Kressler C, Yagita H, Agata Y, Vooijs M, Hamazaki Y, Inoue J, Minato N.
Title Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia.
Journal Sci Rep
Abstract The Rap G protein signal regulates Notch activation in early thymic progenitor cells, and deregulated Rap activation (Rap(high)) results in the development of Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL). We demonstrate that the Rap signal is required for the proliferation and leukemogenesis of established Notch-dependent T-ALL cell lines. Attenuation of the Rap signal by the expression of a dominant-negative Rap1A17 or Rap1GAP, Sipa1, in a T-ALL cell line resulted in the reduced Notch processing at site 2 due to impaired maturation of Adam10. Inhibition of the Rap1 prenylation with a geranylgeranyl transferase inhibitor abrogated its membrane-anchoring to Golgi-network and caused reduced proprotein convertase activity required for Adam10 maturation. Exogenous expression of a mature form of Adam10 overcame the Sipa1-induced inhibition of T-ALL cell proliferation. T-ALL cell lines expressed Notch ligands in a Notch-signal dependent manner, which contributed to the cell-autonomous Notch activation. Although the initial thymic blast cells barely expressed Notch ligands during the T-ALL development from Rap(high) hematopoietic progenitors in vivo, the ligands were clearly expressed in the T-ALL cells invading extrathymic vital organs. These results reveal a crucial role of the Rap signal in the Notch-dependent T-ALL development and the progression.
Volume 5
Pages 7978
Published 2015-1-23
DOI 10.1038/srep07978
PII srep07978
PMID 25613394
PMC PMC4303867
MeSH Animals Cell Line, Tumor Cell Proliferation* GTPase-Activating Proteins / genetics GTPase-Activating Proteins / metabolism* Mice Mice, Knockout Nuclear Proteins / genetics Nuclear Proteins / metabolism* Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism* Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction* rap1 GTP-Binding Proteins / genetics rap1 GTP-Binding Proteins / metabolism*
IF 3.998
Human and Animal Cells TALL-1(RCB2084)