title: Control of nuclear HIPK2 localization and function by a SUMO interaction motif.
abstract: The serine/threonine kinase HIPK2 regulates gene expression programs controlling differentiation and cell death. HIPK2 localizes in subnuclear speckles, but the structural components allowing this localization are not understood. A point mutation analysis allowed mapping two nuclear localization signals and a SUMO interaction motif (SIM) that also occurs in HIPK1 and HIPK3. The SIM binds all three major isoforms of SUMO (SUMO-1-3), while only SUMO-1 is capable of covalent conjugation to HIPK2. Deletion or mutation of the SIM prevented SUMO binding and precluded localization of HIPK2 in nuclear speckles, thus causing localization of HIPK2 to the entire cell. Functional inactivation of the SIM prohibited recruitment of HIPK2 to PML nuclear bodies and disrupted colocalization with other proteins such as the polycomb protein Pc2 in nuclear speckles. Interaction of HIPK2 with Pc2 or PML in intact cells was largely dependent on a functional SIM in HIPK2, highlighting the relevance of SUMO/SIM interactions as a molecular glue that serves to enhance protein/protein interaction networks. HIPK2 mutants with an inactive SIM showed changed activities, thus revealing that non-covalent binding of SUMO to the kinase is important for the regulation of its function.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, 35392 Giessen, Germany.
authors.forename: Laureano
authors.initials: L
authors.lastname: de la Vega
authors.forename: Katrin
authors.initials: K
authors.lastname: Fröbius
authors.forename: Rita
authors.initials: R
authors.lastname: Moreno
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.forename: Hui
authors.initials: H
authors.lastname: Geng
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008025:Ligases; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; C115114:HIPK2 protein, human; C543644:HIPK1 protein, human; C109102:HIPK3 protein, human; D017346:Protein Serine-Threonine Kinases; D008025:Ligases; C570427:CBX4 protein, human