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Biochim Biophys Acta Mol Cell Res. 2018 Apr;1865(4):551-559. doi: 10.1016/j.bbamcr.2018.01.004. Epub 2018 Jan 6.

Insulin-induced translocation of IR to the nucleus in insulin responsive cells requires a nuclear translocation sequence.

Author information

1
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
2
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: sansampson@gmail.com.

Abstract

Insulin binding to its cell surface receptor (IR) activates a cascade of events leading to its biological effects. The Insulin-IR complex is rapidly internalized and then is either recycled back to the plasma membrane or sent to lysosomes for degradation. Although most of the receptor is recycled or degraded, a small amount may escape this pathway and migrate to the nucleus of the cell where it might be important in promulgation of receptor signals. In this study we explored the mechanism by which insulin induces IR translocation to the cell nucleus. Experiments were performed cultured L6 myoblasts, AML liver cells and 3T3-L1 adipocytes. Insulin treatment induced a rapid increase in nuclear IR protein levels within 2 to 5 min. Treatment with WGA, an inhibitor of nuclear import, reduced insulin-induced increases nuclear IR protein; IR was, however, translocated to a perinuclear location. Bioinformatics tools predicted a potential nuclear localization sequence (NLS) on IR. Immunofluorescence staining showed that a point mutation on the predicted NLS blocked insulin-induced IR nuclear translocation. In addition, blockade of nuclear IR activation in isolated nuclei by an IR blocking antibody abrogated insulin-induced increases in IR tyrosine phosphorylation and nuclear PKCδ levels. Furthermore, over expression of mutated IR reduced insulin-induced glucose uptake and PKB phosphorylation. When added to isolated nuclei, insulin induced IR phosphorylation but had no effect on nuclear IR protein levels. These results raise questions regarding the possible role of nuclear IR in IR signaling and insulin resistance.

KEYWORDS:

Insulin receptor; Insulin signaling; Nuclear Location Sequence; Nuclear translocation

PMID:
29317261
DOI:
10.1016/j.bbamcr.2018.01.004
[Indexed for MEDLINE]
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