文摘
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Summary
Transforming growth factor ¦Â (TGF-¦Â) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-¦Â 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-¦Â signaling by neddylating and stabilizing the type II receptor (T¦ÂRII). Knockout of c-Cbl decreases the T¦ÂRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-¦Â stimulation, while c-Cbl overexpression stabilizes T¦ÂRII and sensitizes leukemia cells to TGF-¦Â. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to T¦ÂRII at Lys556 and Lys567. Neddylation of T¦ÂRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting T¦ÂRII ubiquitination and degradation. We have also identified?a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant T¦ÂRII neddylation and leukemia development.
