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

Dov Kesten, Miriam Horovitz-Fried, Tamar Brutman-Barazani, Sanford R. Sampson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)551-559
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1865
Issue number4
DOIs
StatePublished - Apr 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier B.V.

Funding

This work was supported in part by grants from DCure-Diabetes Cure Israel.

FundersFunder number
DCure-Diabetes Cure Israel

    Keywords

    • Insulin receptor
    • Insulin signaling
    • Nuclear Location Sequence
    • Nuclear translocation

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