The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase.
The c-Jun and c-Myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-Myc, we report here that phosphorylation of c-Jun by GSK3 creates a high-affinity binding site for the E3 ligase Fbw7, which targets c-Jun for polyubiquitination and proteasomal degradation. In keeping with this, we found that c-Jun levels were inversely related to GSK3 activity in mammalian cells that had entered the cell cycle. Importantly, phosphorylation of c-Jun by GSK3 requires a priming phosphorylation event at Ser-243. Ser-243 is mutated to phenylalanine in v-Jun and allows it to escape recognition by Fbw7. These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc.
Wei
Wenyi
W
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Jin
Jianping
J
Schlisio
Susanne
S
Harper
J Wade
JW
Kaelin
William G
WG
D001665:Binding Sites; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics* / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics; D010766:Phosphorylation; D017354:Point Mutation; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000737:chemistry / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016759:Oncogene Protein p65(gag-jun); D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D025801:Ubiquitin; D012694:Serine; D010649:Phenylalanine; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3; D008025:Ligases