Identification and characterization of a general nuclear translocation signal in signaling proteins

Mol Cell. 2008 Sep 26;31(6):850-61. doi: 10.1016/j.molcel.2008.08.007. Epub 2008 Sep 4.


Upon stimulation, many proteins translocate into the nucleus in order to regulate a variety of cellular processes. The mechanism underlying the translocation is not clear since many of these proteins lack a canonical nuclear localization signal (NLS). We searched for an alternative mechanism in extracellular signal-regulated kinase (ERK)-2 and identified a 3 amino acid domain (SPS) that is phosphorylated upon stimulation to induce nuclear translocation of ERK2. A 19 amino acid stretch containing this phosphorylated domain inserts nondiffusible proteins to the nucleus autonomously. The phosphorylated SPS acts by binding to importin7 and the release from nuclear pore proteins. This allows its functioning both in passive and active ERK transports. A similar domain appears in many cytonuclear shuttling proteins, and we found that phosphorylation of similar sequences in SMAD3 or MEK1 also induces their nuclear accumulation. Therefore, our findings show that this phosphorylated domain acts as a general nuclear translocation signal (NTS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antibody Specificity
  • COS Cells
  • Cell Nucleus / enzymology*
  • Chlorocebus aethiops
  • HeLa Cells
  • Humans
  • Karyopherins / metabolism
  • MAP Kinase Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 1 / chemistry*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Molecular Sequence Data
  • Nuclear Localization Signals / metabolism*
  • Nuclear Pore Complex Proteins / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Smad3 Protein / chemistry
  • Smad3 Protein / metabolism
  • beta-Galactosidase / metabolism


  • IPO7 protein, human
  • Karyopherins
  • Nuclear Localization Signals
  • Nuclear Pore Complex Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Smad3 Protein
  • Phosphoserine
  • Mitogen-Activated Protein Kinase 1
  • MAP Kinase Kinase 1
  • beta-Galactosidase