title: Phosphorylation of the N-terminal domain of p48 Ebp1 by CDK2 is required for tumorigenic function of p48.
abstract: The long isoform of ErbB3 binding protein 1 (Ebp1), p48, strongly promotes tumorigenesis of glioblastoma, accelerating cell proliferation and transformation, while the short isoform, p42, which lacks the N-terminal 54 amino acids, inhibits tumor growth. However, it is unclear if the N-terminal domain of p48 regulates the oncogenic function of p48. Here, we show that p48, but not p42, interacts with cyclin-dependent kinase 2 (CDK2) through its N-terminal domain, resulting in the specific phosphorylation of serine 34 of p48. Overexpression of wild-type p48 greatly enhanced tumor cell growth, whereas phospho-ablated mutant S34A of p48, which is mutated at the CDK2 phosphorylation site, antagonizes cell proliferation and transformation. Moreover, phospho-ablated mutant S34A abrogated the ability of p48 to accelerate tumor cell growth in a mouse engraft model. Thus, our findings indicate that p48Ebp1 acts as an oncoprotein through selective interaction and/or modification of the N-terminal domain that does not exist in its short isoform p42.
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Hyo Rim
authors.initials: HR
authors.lastname: Ko
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Jee-Yin
authors.initials: JY
authors.lastname: Ahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D014170:Transformation, Genetic / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101633:PA2G4 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; Ebp1; cancer