Differential subcellular localization of insulin receptor substrates depends on C-terminal regions and importin beta.
Insulin receptor substrates (IRSs) play essential roles in signal transduction of insulin and insulin-like growth factors. Previously, we showed that IRS-3 is localized to the nucleus as well as the cytosol, while IRS-1 and 2 are mainly localized to the cytoplasm. In the present study, we found that importin beta directly interacts with IRS-3 and is able to mediate nuclear transport of IRS-3. Importin beta interacted with the pleckstrin homology domain, the phosphotyrosine binding domain and the C-terminal region of IRS-3; indeed all of these fragments exhibited predominant nuclear localization. By contrast, almost no interaction of importin beta with IRS-1 and -2 was observed, and their C-terminal regions displayed discrete spotty images in the cytosol. In addition, using chimeric proteins between IRS-1 and IRS-3, we revealed that the C-terminal regions are the main determinants of the differing subcellular localizations of IRS-1 and IRS-3.
Laboratory of Cell Regulation, Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Tomohiro
T
Kabuta
Kazumi
K
Take
Chihana
C
Kabuta
Fumihiko
F
Hakuno
Shin-ichiro
S
Takahashi
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D009154:Mutation; D019000:Phosphotyrosine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism*
D028961:beta Karyopherins; D019000:Phosphotyrosine; D011972:Receptor, Insulin