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C-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor

Title
C-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor
Authors
Zuo W.Huang F.Chiang Y.J.Li M.Du J.Ding Y.Zhang T.Lee H.W.Jeong L.S.Chen Y.Deng H.Feng X.-H.Luo S.Gao C.Chen Y.-G.
Ewha Authors
정낙신이혁우
Issue Date
2013
Journal Title
Molecular Cell
ISSN
1097-2765JCR Link
Citation
vol. 49, no. 3, pp. 499 - 510
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Transforming growth factor β (TGF-β) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-β signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-β signaling by neddylating and stabilizing the type II receptor (TβRII). Knockout of c-Cbl decreases the TβRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-β stimulation, while c-Cbl overexpression stabilizes TβRII and sensitizes leukemia cells to TGF-β. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to TβRII at Lys556 and Lys567. Neddylation of TβRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting TβRII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant TβRII neddylation and leukemia development. © 2013 Elsevier Inc.
DOI
10.1016/j.molcel.2012.12.002
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약학대학 > 약학과 > Journal papers
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