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Transforming growth factor β (TGF-β) is a potent anti-proliferative factor in multiple types of cells.Deregulation of TGF-β signaling is associated with development of many cancers including leukemia while the molecular mechanisms are largely unclear.We show that c-Cbl, a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-β signaling by neddylating and stabilizing the type Ⅱ receptor (TβRⅡ).