Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification

J Biol Chem. 2005 Aug 12;280(32):29224-32. doi: 10.1074/jbc.M503921200. Epub 2005 Jun 15.

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is involved in transcriptional regulation, growth suppression, and apoptosis. Previous reports showed that HIPK2 can signal cell death via p53, and independently of p53 by activating the c-Jun NH2-terminal kinase (JNK) pathway or mediating CtBP degradation. Here we demonstrate that human HIPK2 is small ubiquitin-related modifier-1 (SUMO-1)-modified in vitro and in vivo at lysine residue 25, a SUMO consensus modification motif conserved in human and mouse HIPK family proteins. SUMO modification of HIPK2 altered neither its nuclear body localization nor its recruitment to promyelocytic leukemia-nuclear bodies. However, SUMO-1 modification inhibited HIPK2-induced JNK activation and p53-independent antiproliferative function. HIPK2 with a mutated SUMO acceptor lysine residue was refractory to inhibition of HIPK2-mediated JNK activation by SUMO-1. Furthermore, we demonstrate that SUMO protease SuPr-1 interacts with HIPK2, and both proteins predominantly colocalize in promyelocytic leukemia-nuclear bodies. SuPr-1 deconjugates SUMO-1 from HIPK2 in vitro and in vivo, which results in modestly increased HIPK2-induced JNK activity. Thus, our data demonstrate that HIPK2 effector function on JNK is modulated through dynamic SUMO-1 modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Apoptosis
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • Luciferases / metabolism
  • Lysine / chemistry
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Protein Binding
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • SUMO-1 Protein / metabolism*
  • Signal Transduction
  • Transfection

Substances

  • Carrier Proteins
  • SUMO-1 Protein
  • Luciferases
  • HIPK2 protein, human
  • Protein Serine-Threonine Kinases
  • Lysine