Ebp1 association with nucleophosmin/B23 is essential for regulating cell proliferation and suppressing apoptosis.
Ebp1 and NPM/B23 are essential for cell proliferation and survival. Ebp1 possesses p42 and p48 isoforms. Whereas p42 exclusively resides in the cytoplasm, p48 localizes in both the cytoplasm and the nucleolus. Here, we show that Ebp1 forms a complex with B23, and this complex plays a critical role in cell proliferation and survival. p42 specifically associates with B23 upon epidermal growth factor stimulation, while p48 constantly binds B23. Moreover, Ser360 phosphorylation in p42, but not p48, is critical for the interaction. p48 constitutively binds B23 in the nucleolus, for which B23 Lys263 sumoylation is indispensable. By contrast, p42 selectively binds unsumoylated B23 mutants. Interestingly, B23 K263R, an unsumoylated mutant, triggers p42 nuclear translocation and interacts with it in the nucleus even in the absence of epidermal growth factor. In contrast, the nucleolar residency of p48 is abolished in B23 K263R cells. During the cell cycle, p42 selectively colocalizes with B23 in the mitotic cells, correlating with its phosphorylation status in mitosis. Knocking down of B23 or Ebp1 substantially decreases ribosome biogenesis and cell survival. Thus, B23 distinctively binds Ebp1 isoforms and regulates cell proliferation and survival through p42 and p48, respectively.
Okada
Masashi
M
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Jang
Sung-Wuk
SW
Ye
Keqiang
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051034:Inhibitor of Apoptosis Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; C101633:PA2G4 protein, human; C511885:PA2G4 protein, rat; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D025842:SUMO-1 Protein; D000090243:Nucleophosmin; D004815:Epidermal Growth Factor