Beta Like Importins Mediate the Nuclear Translocation of MAPKs.
BACKGROUND/AIMS The rapid nuclear translocation of signaling proteins upon stimulation is important for the regulation of de novo gene expression. However, the molecular mechanisms of this translocation is not well understood, although some studies suggest that much of this translocation may be mediated by beta like importins (Imps) Here we undertook to study the stimulated nuclear shuttling of JNK and p38 MAPKs. METHODS For this purpose, we used coimmunoprecipitation, proximity ligation assay, gel filtration and immunostaining to examine the mechanism of nuclear translocation of these proteins. RESULTS We found that JNK and p38 MAPKs translocate into the nucleus in a Ran dependent, but NLS or NTS independent manner, unrelated to their catalytic activity. We show that this translocation involves three b like Imps, 3, 7 and 9. Knockdown of these Imps inhibits the nuclear translocation of the MAPKs, and thereby, phosphorylation of their transcription factor targets. We further demonstrate that the translocation requires the stimulated formation of heterotrimers composed of Imp3/Imp7/MAPK or Imp3/Imp9/MAPK. JNK1/2 and p38a/b bind to either Imp7 or Imp9 upon stimulated post translational modifications of the two Imps, while Imp3 joins the complex after its stimulation induced phosphorylation. Once formed, these heterotrimers move to the nuclear envelope where Imp3 remains, while Imp7 or Imp9 escort the MAPKs into the nucleus. CONCLUSION These results suggest that b like Imps are central mediators of stimulated nuclear translocation of signaling proteins, providing a central level of regulation of the induction of cellular processes such as transcription upon stimulation.
Cellular physiology and biochemistry international journal of experimental cellular physiology, biochemistry, and pharmacology