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Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A
Morcavallo, Alaide Genua, Marco Palummo, Angela Kletvikova, Emilia Jiracek, Jiri Brzozowski, Andrzej M. Iozzo, Renato V. Belfiore, Antonino
Morcavallo, Alaide
Genua, Marco
Palummo, Angela
Kletvikova, Emilia
Jiracek, Jiri
Brzozowski, Andrzej M.
Iozzo, Renato V.
Belfiore, Antonino
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Journal article
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2012-03-30
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Biology
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https://doi.org/10.1074/jbc.m111.252478
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.
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Alaide Morcavallo, Marco Genua, Angela Palummo, Emilia Kletvikova, Jiri Jiracek, Andrzej M. Brzozowski, Renato V. Iozzo, Antonino Belfiore, Andrea Morrione. Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A*, Journal of Biological Chemistry, 287,(14), 2012, 11422-11436, ISSN 0021-9258, https://doi.org/10.1074/jbc.M111.252478.
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Elsevier
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Journal of Biological Chemistry, Vol. 287, No. 14
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