Rapid Insulin-Dependent Endocytosis of the Insulin Receptor by Caveolae in Primary Adipocytes

Fagerholm, Siri; Örtegren, Unn; Karlsson, Matts; Ruishalme, Iida; Strålfors, Peter

doi:10.1371/journal.pone.0005985

Cited by 105 publications

(89 citation statements)

References 79 publications

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“…For example, the binding of certain cargo (e.g. LacCer, insulin) increases Cav1 Tyr 14 phosphorylation as well as stimulating internalization of caveolae (23,36). In addition, other factors such as oxidative stress, hyperosmotic stress, shear stress, and UV light have all been reported to induce Cav1 phosphorylation (21,37,38).…”

Section: Discussionmentioning

confidence: 99%

Co-regulation of Caveolar and Cdc42-dependent Fluid Phase Endocytosis by Phosphocaveolin-1

Cheng¹,

Singh²,

Holicky

et al. 2010

Journal of Biological Chemistry

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Several clathrin-independent endocytosis mechanisms have been identified that can be distinguished by specific requirements for certain proteins, such as caveolin-1 (Cav1) and the Rho GTPases, RhoA and Cdc42, as well as by specific cargo. Some endocytic pathways may be co-regulated such that disruption of one pathway leads to the upregulation of another; however, the underlying mechanisms for this are unclear. Cav1 has been reported to function as a guanine nucleotide dissociation inhibitor (GDI), which inhibits Cdc42 activation. We tested the hypothesis that Cav1 can regulate Cdc42-dependent, fluid phase endocytosis. We demonstrate that Cav1 overexpression decreases fluid phase endocytosis, whereas silencing of Cav1 enhances this pathway. Enhancement of Cav1 phosphorylation using a phosphatase inhibitor reduces Cdc42-regulated pinocytosis while stimulating caveolar endocytosis. Fluid phase endocytosis was inhibited by expression of a putative phosphomimetic mutant, Cav1-Y14E, but not by the phospho-deficient mutant, Cav1-Y14F. Overexpression of Cav2, or a Cav1 mutant in which the GDI region was altered to the corresponding sequence in Cav2, did not suppress fluid phase endocytosis. These results suggest that the Cav1 expression level and phosphorylation state regulates fluid phase endocytosis via the interaction between the Cav1 GDI region and Cdc42. These data define a novel molecular mechanism for co-regulation of two distinct clathrin-independent endocytic pathways.It is now widely recognized that multiple clathrin-independent mechanisms of endocytosis exist in addition to the classical process of clathrin-mediated internalization (1, 2). Two of the better characterized clathrin-independent endocytic pathways are caveolar endocytosis and fluid phase pinocytosis. The first of these mechanisms is mediated by caveolae, 50 -80-nm flaskshaped invaginations at the plasma membrane (PM), 4 which are enriched in sphingolipids and cholesterol and marked by the presence of a caveolin protein, usually caveolin-1 (Cav1) (3). Endocytosis through caveolae is promoted by ligand binding and is dynamin-dependent (4 -7). Cargo may include some viruses, bacteria, albumin, cholera toxin, fluorescent glycosphingolipids, and antibody-clustered GPI-anchored proteins (1,3,8). Another well recognized clathrin-independent pathway is fluid phase endocytosis, which is dynamin-independent and is regulated by the small GTPase, Cdc42, as well as by Arf1(1, 9, 10). This pathway is responsible for internalization of unclustered GPI-anchored proteins that are initially detected in tubular invaginations from the PM and that internalize large volumes of fluid with each budding event (9, 11). Previous studies have suggested that some endocytic pathways may be co-regulated such that inhibition of one leads to the up-regulation of another (12, 13); however, the underlying mechanisms responsible for such co-regulation are not known. Recently, it has been shown that Cav1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor (GDI) in p...

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Section: Discussionmentioning

confidence: 99%

Co-regulation of Caveolar and Cdc42-dependent Fluid Phase Endocytosis by Phosphocaveolin-1

Cheng¹,

Singh²,

Holicky

et al. 2010

Journal of Biological Chemistry

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“…The faster responding pool transmitted a fast signal to IRS1 while the slower pool was the dominating IR pool. However, this explanation required a large pool of internalized receptors, which we have previously shown is not the case [39]. A modified two pool hypothesis with limiting IRS1 concentration and specific IR-IRS1 binding could explain the reversed order of peaks of IR and IRS1.…”

Section: Figure 8: Insulin Receptor Internalizationmentioning

confidence: 68%

“…After insulin binding and activation the insulin receptor will be rapidly internalized into the cell via small invaginations of the plasma membrane (caveolae) [39] (Figure 8). The internalized IR dissociates from insulin and dephosphorylation occurs before the inactive form of IR is recycled back to the plasma membrane [40,41].…”

Section: Insulin Receptor Internalization and Activation Of Irs1mentioning

confidence: 99%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant.The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments.We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells.In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes -and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state -an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV). Populärvetenskaplig sammanfattningTyp 2-diabetes är en vanligt förekommande sjukdom där kroppens vävnader förlorar sin känslighet mot hormonet insulin. Insulinets uppgift är att hålla en jämn blodsockernivå dygnet runt. Insulin utsöndras i samband med måltider och påverkar muskel-och fettvävnader att ta upp socker och levern att sluta producera socker. Det är viktigt att hålla en jämn blodsockernivå eftersom låga nivåer kan vara direkt dödligt och höga nivåer är skadligt för blodkärlen, vilket i sin tur kan led...

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“…Insulin is internalized with caveolin 1 in vascular endothelial cells [36]. This process is facilitated by actin filaments through PI3K/Akt pathway [37].…”

Section: Caveolinsmentioning

confidence: 99%

Insulin Delivery: An Ever Changing Frontier

Janjua¹

2016

JED

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Insulin transport across vascular endothelial cells is the rate limiting step in its time action profile. Glucose uptake in response to insulin is estimated through different techniques and is influenced by insulin sensitivity of the tissue. Glucose clamp technique and minimal model imply an incremental increase in the levels of insulin in the ISF compartment evidenced by increase in glucose uptake. This can not merely be explanied by tissue capillary recruitment or increase in blood flow of already perfused areas. Although insulin is proven to affect the blood flow and capillary recruitment of already perfused areas, restoration of muscle blood flow in insulin resistant patients does not revert the insulin activity profile. By review of frequently cited articles, it can be interpreted that insulin causes a much greater increase in tissue recruitment by increasing the perfused capillary volume of previously unperfused areas, an increase in the permeability of the capillaries and recruitment of insulin transport receptors. This also results in an Increase in volume of distribution of glucose. Insulin, like other proteins, may be transported across by simple diffusion, paracellular pathway and transcellular pathway with the help of transport receptors. In conclusion, insulin is most likely transported across capillary endothelial cells by more than one mechanism and there may be recruitment of these pathways according to insulin levels. Thus further investigations of these possible pathways may help pave the way for more efficient insulin delivery methods in the future.

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Rapid Insulin-Dependent Endocytosis of the Insulin Receptor by Caveolae in Primary Adipocytes

Cited by 105 publications

References 79 publications

Co-regulation of Caveolar and Cdc42-dependent Fluid Phase Endocytosis by Phosphocaveolin-1

Co-regulation of Caveolar and Cdc42-dependent Fluid Phase Endocytosis by Phosphocaveolin-1

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Insulin Delivery: An Ever Changing Frontier

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