title: Novel Serine 176 Phosphorylation of YBX1 Activates NF-κB in Colon Cancer.
abstract: Y box protein 1 (YBX1) is a well known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Previously, we have shown that YBX1 could function as a tumor promoter through phosphorylation of its Ser-165 residue, leading to the activation of the NF-κB signaling pathway (1). In this study, using mass spectrometry analysis, we discovered a distinct phosphorylation site, Ser-176, on YBX1. Overexpression of the YBX1-S176A (serine-to-alanine) mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB-activating ability compared with that of WT-YBX1, confirming that Ser-176 phosphorylation is critical for the activation of NF-κB by YBX1. Importantly, the mutant of Ser-176 and the previously reported Ser-165 sites regulate distinct groups of NF-κB target genes, suggesting the unique and irreplaceable function of each of these two phosphorylated serine residues. Our important findings could provide a novel cancer therapy strategy by blocking either Ser-176 or Ser-165 phosphorylation or both of YBX1 in colon cancer.
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Laiqing
authors.initials: L
authors.lastname: Hua
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Benlian
authors.initials: B
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Han
authors.initials: H
authors.lastname: Wei
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Prabhu
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Antja-Voy
authors.initials: AV
authors.lastname: Hartley
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Guanglong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Pharmacology and Toxicology; Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Biochemistry and Molecular Biology. Electronic address: lut@iupui.edu.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000032:analysis / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000032:analysis / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D012694:Serine
keywords: NF-κB; YBX1; colon cancer; phosphorylation; posttranslational modification (PTM); serine