Nuclear Translocation

Entry Code

Science Signaling  30 Sep 2008:
Vol. 1, Issue 39, pp. ec338
DOI: 10.1126/scisignal.139ec338

The timely translocation of various signaling proteins from the cytoplasm to the nucleus is essential to their function. Many proteins that are targeted to the nucleus contain a canonical nuclear localization signal (NLS) or bind to another protein that contains an NLS. For those signaling proteins that do not contain an NLS, such as the extracellular signal-regulated kinases (ERKs) and SMADs, how they translocate to the nucleus is unclear. Chuderland et al. performed Western blotting and fluorescence microscopy experiments to demonstrate that a Ser-Pro-Ser (SPS) sequence in ERK2 was phosphorylated upon cellular stimulation and was required for the nuclear translocation of ERK2. Mutation of the SPS sequence to Ala-Pro-Ala, which cannot undergo phosphorylation, blocked nuclear translocation of ERK, whereas mutation to Glu-Pro-Glu, which mimics the phosphorylated SPS sequence, resulted in constitutive nuclear translocation of ERK2. Phosphorylation of SPS was independent of phosphorylation of the Thr-Glu-Tyr motif that is necessary to activate ERKs. SPS phosphorylation was required for the interaction of ERK2 with the nuclear import protein importin7. The authors extended their findings to other signaling molecules, including SMAD3, whose SPS sequence was phosphorylated in response to transforming growth factor-β (TGF-β) and was necessary for its interaction with importin7, and MEK1, a mitogen-activated protein kinase kinase, whose Thr-Pro-Thr sequence played a role in its nuclear translocation. Although the kinases responsible for SPS phosphorylation were not identified, the authors suggest that SPS may act as a general nuclear translocation signal for the NLS-independent translocation of various signaling molecules to the nucleus.

D. Chuderland, A. Konson, R. Seger, Identification and characterization of a general nuclear translocation signal in signaling proteins. Mol. Cell 31, 850-861 (2008). [PubMed]