caa a22 4500 606174680 CHVBK 20210128100739.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s00018-014-1665-5 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1665-5 The F-box protein FBXO7 positively regulates bone morphogenetic protein-mediated signaling through Lys-63-specific ubiquitination of neurotrophin receptor-interacting MAGE (NRAGE) [Elektronische Daten] [Jengmin Kang, Kwang Chung] Parkinson's disease (PD) is characterized by progressive midbrain dopaminergic neuron degeneration and the formation of intracellular protein aggregates, referred to as Lewy bodies. F-box only protein 7 (FBXO7) gene mutations are closely associated with progression of the autosomal recessive form of familial PD. FBXO7 encodes a component of Skp1, cullin, F-box ubiquitin ligase complexes; however, its cellular targets, including substrates and regulators, are not yet clarified. To identify potential substrates of FBXO7, we performed a yeast two-hybrid screen of a human fetal brain library and identified neurotrophin receptor-interacting MAGE protein (NRAGE) as a novel FBXO7-binding partner. We found that FBXO7 interacts with NRAGE and mediates Lys-63-linked poly-ubiquitination of NRAGE in mammalian cells. FBXO7 overexpression accelerates formation of NRAGE-TAK1-TAB1 complexes, whereas FBXO7 knockdown correspondingly decreases complex formation. In addition, BMP4 stimulation enhances NRAGE ubiquitination through FBXO7 and facilitates endogenous NRAGE-TAK1-TAB1 complex formation. Furthermore, FBXO7 positively regulates formation of the BMP receptor-NRAGE-TAK1-TAB1 complex, and up-regulates NF-κB activity. Taken together, our results suggest that FBXO7 affects BMP4-mediated signaling through proteasome-independent ubiquitination of NRAGE and augments formation of downstream signaling components. Springer Basel, 2014 BMP nationallicence FBXO7 nationallicence NF-κB nationallicence NRAGE nationallicence Parkinson disease nationallicence TAB1 nationallicence TAK1 nationallicence Ubiquitination nationallicence BMP : Bone morphogenetic protein nationallicence BMPR : BMP receptor nationallicence DAPI : 4,6-Diamidino-2-phenylindole nationallicence DMEM : Dulbecco's modified Eagle's medium nationallicence ECL : Enhanced chemiluminescence nationallicence FBP : F-box protein nationallicence FBS : Fetal bovine serum nationallicence FBXO7 : F-box only protein 7 nationallicence HEK293 : Human embryonic kidney 293 nationallicence MAGE : Melanoma-associated antigens nationallicence NRAGE : Neurotrophin receptor-interacting MAGE protein nationallicence P19 : P19 embryonic carcinoma nationallicence PBS : Phosphate-buffered saline nationallicence PD : Parkinson's disease nationallicence PI31 : Proteasome inhibitor subunit 1 nationallicence SCF : Skp1-cullin1-F box protein nationallicence Ubl : Ubiquitin-like nationallicence Kang Jengmin Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Yonsei-ro 50, Seodaemun-gu, 120-749, Seoul, Korea aut Chung Kwang Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Yonsei-ro 50, Seodaemun-gu, 120-749, Seoul, Korea aut Cellular and Molecular Life Sciences Springer Basel 72/1(2015-01-01), 181-195 1420-682X 72:1<181 2015 72 18 https://doi.org/10.1007/s00018-014-1665-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1665-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kang Jengmin Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Yonsei-ro 50, Seodaemun-gu, 120-749, Seoul, Korea aut NATIONALLICENCE 700 1- Chung Kwang Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Yonsei-ro 50, Seodaemun-gu, 120-749, Seoul, Korea aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/1(2015-01-01), 181-195 1420-682X 72:1<181 2015 72 18