Revising Endosomal Trafficking under Insulin Receptor Activation

Iraburu, María J.; Garner, Tommy; Montiel-Duarte, Cristina

doi:10.3390/ijms22136978

Cited by 21 publications

(16 citation statements)

References 86 publications

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“…These pathways regulate glucose uptake, lipogenesis, gluconeogenesis, glycogen synthesis, and cellular proliferation 1,2,9 . The active IR is internalized by endocytosis and is either degraded in lysosomes, recycled back to the plasma membrane, or transported into the nucleus where it becomes associated with insulin-responsive genes [10][11][12][13][14][15][16] .…”

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confidence: 99%

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

et al. 2022

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Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.

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confidence: 99%

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

et al. 2022

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“…Regarding AKT activity, it has been recently found that the mTORC1 complex is inactivated in OCRL1 deficient cells ( Madhivanan et al, 2020 ), a defect that triggers a lack of nutrient-sensing ( Wang et al, 2021 ) due to mTORC1 is required for proper insulin signaling ( Saltiel and Kahn, 2001 ). Insulin signaling is also highly dependent on the cell type, something we observed in our experiments, and is associated with insulin receptor trafficking ( Iraburu et al, 2021 ). For instance, the activation of PI3K and pAKT takes place at the plasma membrane as well as in endosomes, with higher activation at the endosome ( Ceresa et al, 1998 ; Iraburu et al, 2021 ), being possible that under LS conditions at least the endosomal signaling, would be affected.…”

Section: Discussionmentioning

confidence: 67%

“…Insulin signaling is also highly dependent on the cell type, something we observed in our experiments, and is associated with insulin receptor trafficking ( Iraburu et al, 2021 ). For instance, the activation of PI3K and pAKT takes place at the plasma membrane as well as in endosomes, with higher activation at the endosome ( Ceresa et al, 1998 ; Iraburu et al, 2021 ), being possible that under LS conditions at least the endosomal signaling, would be affected. Therefore, it is expected that the response to insulin and megalin phosphorylation mediated by GSK3ß are affected in LS cellular models and, in general, cells with decreased function of OCRL1 would be less responsive to insulin.…”

Section: Discussionmentioning

confidence: 67%

Participation of OCRL1, and APPL1, in the expression, proteolysis, phosphorylation and endosomal trafficking of megalin: Implications for Lowe Syndrome

Sandoval

Fuentealba²,

Marzolo³

2022

Front. Cell Dev. Biol.

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Megalin/LRP2 is the primary multiligand receptor for the re-absorption of low molecular weight proteins in the proximal renal tubule. Its function is significantly dependent on its endosomal trafficking. Megalin recycling from endosomal compartments is altered in an X-linked disease called Lowe Syndrome (LS), caused by mutations in the gene encoding for the phosphatidylinositol 5-phosphatase OCRL1. LS patients show increased low-molecular-weight proteins with reduced levels of megalin ectodomain in the urine and accumulation of the receptor in endosomal compartments of the proximal tubule cells. To gain insight into the deregulation of megalin in the LS condition, we silenced OCRL1 in different cell lines to evaluate megalin expression finding that it is post-transcriptionally regulated. As an indication of megalin proteolysis, we detect the ectodomain of the receptor in the culture media. Remarkably, in OCRL1 silenced cells, megalin ectodomain secretion appeared significantly reduced, according to the observation in the urine of LS patients. Besides, the silencing of APPL1, a Rab5 effector associated with OCRL1 in endocytic vesicles, also reduced the presence of megalin’s ectodomain in the culture media. In both silencing conditions, megalin cell surface levels were significantly decreased. Considering that GSK3ß-mediated megalin phosphorylation reduces receptor recycling, we determined that the endosomal distribution of megalin depends on its phosphorylation status and OCRL1 function. As a physiologic regulator of GSK3ß, we focused on insulin signaling that reduces kinase activity. Accordingly, megalin phosphorylation was significantly reduced by insulin in wild-type cells. Moreover, even though in cells with low activity of OCRL1 the insulin response was reduced, the phosphorylation of megalin was significantly decreased and the receptor at the cell surface increased, suggesting a protective role of insulin in a LS cellular model.

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“…In the acid late endosome, insulin is dissociated from its receptor and is degraded; the role of IDE in this context is discussed [ 6 ]. Then, the insulin receptor can be recycled back to the plasma membrane [ 94 , 95 ] ( Figure 2 b).…”

Section: Ide and The Insulin/insulin-growth Factor Signaling (Iis) Pa...mentioning

confidence: 99%

Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?

Lesire

Leroux

Deprez-Poulain

et al. 2022

Cells

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Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE’s functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics.

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Revising Endosomal Trafficking under Insulin Receptor Activation

Cited by 21 publications

References 86 publications

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

Participation of OCRL1, and APPL1, in the expression, proteolysis, phosphorylation and endosomal trafficking of megalin: Implications for Lowe Syndrome

Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?

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