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Identification of a Phosphorylation-Dependent Nuclear Localization Motif in Interferon Regulatory Factor 2 Binding Protein 2 1,3 1,3 3 3 3 Allen C. T. Teng , Naif A. M. Al-montashiri , Brian L. M. Cheng , Philip Lou , Pinar Ozmizrak , Hsiao- Huei Chen3,4, Alexandre F. R. Stewart1,2,3* 1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada, 2 Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada, 3 University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada, 4 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Abstract Background: Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a muscle-enriched transcription factor required to activate vascular endothelial growth factor-A (VEGFA) expression in muscle. IRF2BP2 is found in the nucleus of cardiac and skeletal muscle cells. During the process of skeletal muscle differentiation, some IRF2BP2 becomes relocated to the cytoplasm, although the functional significance of this relocation and the mechanisms that control nucleocytoplasmic localization of IRF2BP2 are not yet known. Methodology/Principal Findings: Here, by fusing IRF2BP2 to green fluorescent protein and testing a series of deletion and site-directed mutagenesis constructs, we mapped the nuclear localization signal (NLS) to an evolutionarily conserved 354 361 sequence ARKRKPSP in IRF2BP2. This sequence corresponds to a classical nuclear localization motif bearing positively charged arginine and lysine residues. Substitution of arginine and lysine with negatively charged aspartic acid residues blo