Insulin and insulin-like growth factor II differentially regulate endocytic sorting and stability of insulin receptor isoform A

Alaide Morcavallo, Marco Genua, Angela Palummo, Emilia Kletvikova, Jiri Jiracek, Andrzej M. Brzozowski, Renato V. Iozzo, Antonino Belfiore, Andrea Morrione

Research output: Contribution to journalArticle

Abstract

The insulin receptor isoform A (IR-A) binds both insulin and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3-10-fold lower than insulin depending on a cell and tissue context. Notably, in mouse embryonic fibroblasts lacking the IGF-IR and expressing solely the IR-A (R-/IR-A), IGF-II is a more potent mitogen than insulin. As receptor endocytosis and degradation provide spatial and temporal regulation of signaling events, we hypothesized that insulin and IGF-II could affect IR-A biological responses by differentially regulating IR-A trafficking. Using R-/IR-A cells, we discovered that insulin evoked significant IR-A internalization, a process modestly affected by IGF-II. However, the differential internalization was not due to IR-A ubiquitination. Notably, prolonged stimulation of R-/IR-A cells with insulin, but not with IGF-II, targeted the receptor to a degradative pathway. Similarly, the docking protein insulin receptor substrate 1 (IRS-1) was down-regulated after prolonged insulin but not IGF-II exposure. Similar results were also obtained in experiments using [NMeTyrB26]-insulin, an insulin analog with IR-A binding affinity similar to IGF-II. Finally, we discovered that IR-A was internalized through clathrin-dependent and -independent pathways, which differentially regulated the activation of downstream effectors. Collectively, our results suggest that a lower affinity of IGF-II for the IR-A promotes lower IR-A phosphorylation and activation of early downstream effectors vis à vis insulin but may protect IR-A and IRS-1 from down-regulation thereby evoking sustained and robust mitogenic stimuli.

Original languageEnglish
Pages (from-to)11422-11436
Number of pages15
JournalJournal of Biological Chemistry
Volume287
Issue number14
DOIs
Publication statusPublished - Mar 30 2012

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Morcavallo, A., Genua, M., Palummo, A., Kletvikova, E., Jiracek, J., Brzozowski, A. M., Iozzo, R. V., Belfiore, A., & Morrione, A. (2012). Insulin and insulin-like growth factor II differentially regulate endocytic sorting and stability of insulin receptor isoform A. Journal of Biological Chemistry, 287(14), 11422-11436. https://doi.org/10.1074/jbc.M111.252478