Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A

Morcavallo, Alaide; Genua, Marco; Palummo, Angela; Kletvíková, Emília; Jiráček, Jiřı́; Brzozowski, A.M.; Iozzo, Renato V.; Belfiore, Antonino; Morrione, Andrea

doi:10.1074/jbc.m111.252478

Cited by 78 publications

(96 citation statements)

References 68 publications

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“…Endocytic sorting of IR-A differs depending on whether it is activated by insulin or IGF-II. Stimulation with insulin results in the degradation of IR-A and IRS-1, whereas IGF-II protects IR-A and IRS-1 from degradation, which may be responsible for the prolonged activation observed in p70S6 kinase and ERK (33). This evidence supports the role for different ligands, IGF-II, or insulin in this case, producing various effects via the same receptor, IR-A.…”

Section: Discussionsupporting

confidence: 69%

Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion

Ziegler

Chidambaram

Forbes

et al. 2014

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 69%

Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion

Ziegler

Chidambaram

Forbes

et al. 2014

Journal of Biological Chemistry

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“…The mechanisms of this preference are not clear, but analogs with a slow receptor dissociation rate demonstrated more mitogenic signaling (Hansen et al, 1996). The different affinities and binding properties of the insulin analogs may be able to effect IR trafficking and internalization, which can influence levels of ERK activation Morcavallo et al, 2012). However, unlike XMetA, these insulin analogs are all orthosteric binders and, importantly, act as full agonists of the IR, with maximal levels of receptor activation similar to that of insulin.…”

Section: Discussionmentioning

confidence: 99%

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody

Bedinger

Goldfine

Corbin

et al. 2015

J Pharmacol Exp Ther

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The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathwaybiased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.

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“…In further contrast with insulin, all concentrations of IGF1 reduced phosphorylation of ERK relative to control levels in the A. stephensi midgut. Recent work by Morcavallo et al (Morcavallo et al, 2012) suggests how ligand binding at a single receptor could mediate such different responses: phosphorylation of the insulin receptor (IR-A) and downstream Akt and ERK varied with the affinity of the receptor for insulin, insulin analogs and IGF2. When low-affinity ligands bound the receptor, phosphorylation was reduced (compared with high-affinity ligands) and endocytosis-mediated receptor downregulation was inhibited (Morcavallo et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi

Drexler

Nuss

Hauck

et al. 2013

Journal of Experimental Biology

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SUMMARYThe highly conserved insulin/insulin-like growth factor (IGF) signaling (IIS) pathway regulates metabolism, development, lifespan and immunity across a wide range of organisms. Previous studies have shown that human insulin ingested in the blood meal can activate mosquito IIS, resulting in attenuated lifespan and increased malaria parasite infection. Because human IGF1 is present at higher concentrations in blood than insulin and is functionally linked with lifespan and immune processes, we predicted that human IGF1 ingested in a blood meal would affect lifespan and malaria parasite infection in the mosquito Anopheles stephensi. Here we demonstrate that physiological levels of ingested IGF1, like insulin, can persist intact in the blood-filled midgut for up to 30h and disseminate into the mosquito body, and that both peptides activate IIS in mosquito cells and midgut. At these same levels, ingested IGF1 alone extended average mosquito lifespan by 23% compared with controls and, more significantly, when ingested in infected blood meals, reduced the prevalence of Plasmodium falciparum-infected mosquitoes by >20% and parasite load by 35-50% compared with controls. Thus, the effects of ingested IGF1 on mosquito lifespan and immunity are opposite to those of ingested insulin. These results offer the first evidence that insect cells can functionally discriminate between mammalian insulin and IGF1. Further, in light of previous success in genetically targeting IIS to alter mosquito lifespan and malaria parasite transmission, this study indicates that a more complete understanding of the IIS-activating ligands in blood can be used to optimize transgenic strategies for malaria control.

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Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A

Cited by 78 publications

References 68 publications

Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion

Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody

Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi

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