title: c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor.
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.
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zuo
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Y Jeffrey
authors.initials: YJ
authors.lastname: Chiang
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
authors.forename: Chunji
authors.initials: C
authors.lastname: Gao
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002451:Cell Compartmentation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D000075687:NEDD8 Protein; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C513172:Nedd8 protein, mouse; D000090063:Proto-Oncogene Mas; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014452:Ubiquitins; D050721:Proto-Oncogene Proteins c-cbl; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II