The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis

Oncogene. 2021 Mar;40(12):2243-2257. doi: 10.1038/s41388-021-01704-w. Epub 2021 Mar 1.


Mdm2 antagonizes the tumor suppressor p53. Targeting the Mdm2-p53 interaction represents an attractive approach for the treatment of cancers with functional p53. Investigating mechanisms underlying Mdm2-p53 regulation is therefore important. The scaffold protein β-arrestin2 (β-arr2) regulates tumor suppressor p53 by counteracting Mdm2. β-arr2 nucleocytoplasmic shuttling displaces Mdm2 from the nucleus to the cytoplasm resulting in enhanced p53 signaling. β-arr2 is constitutively exported from the nucleus, via a nuclear export signal, but mechanisms regulating its nuclear entry are not completely elucidated. β-arr2 can be SUMOylated, but no information is available on how SUMO may regulate β-arr2 nucleocytoplasmic shuttling. While we found β-arr2 SUMOylation to be dispensable for nuclear import, we identified a non-covalent interaction between SUMO and β-arr2, via a SUMO interaction motif (SIM), that is required for β-arr2 cytonuclear trafficking. This SIM promotes association of β-arr2 with the multimolecular RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub that resides on the cytoplasmic filaments of the nuclear pore complex. Depletion of RanBP2/RanGAP1-SUMO levels result in defective β-arr2 nuclear entry. Mutation of the SIM inhibits β-arr2 nuclear import, its ability to delocalize Mdm2 from the nucleus to the cytoplasm and enhanced p53 signaling in lung and breast tumor cell lines. Thus, a β-arr2 SIM nuclear entry checkpoint, coupled with active β-arr2 nuclear export, regulates its cytonuclear trafficking function to control the Mdm2-p53 signaling axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • GTPase-Activating Proteins / genetics*
  • Humans
  • Mutation / genetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Nuclear Export Signals / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • SUMO-1 Protein / genetics*
  • Signal Transduction / genetics
  • Sumoylation / genetics
  • Tumor Suppressor Protein p53 / genetics*
  • beta-Arrestin 2 / genetics*


  • ARRB2 protein, human
  • GTPase-Activating Proteins
  • Nuclear Export Signals
  • RANGAP1 protein, human
  • SUMO-1 Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • beta-Arrestin 2
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2