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

T G Hofmann, E Jaffray, N Stollberg, R T Hay, H Will

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)29224-29232
Number of pages9
JournalJournal of Biological Chemistry
Volume280
DOIs
Publication statusPublished - 12 Aug 2005

Keywords

  • HOMEODOMAIN-INTERACTING PROTEIN-KINASE-2
  • AXIN-BINDING PROTEIN
  • C-JUN
  • TRANSCRIPTIONAL ACTIVATION
  • COVALENT MODIFICATION
  • NUCLEAR-BODIES
  • BETA-CATENIN
  • P53 ACTIVITY
  • PML
  • UBIQUITIN

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