Caveolin-1-deficient mice show insulin resistance and defective insulin  receptor protein expression in adipose tissue

Cohen, Arnold W.; Razani, Babak; Wang, Xiao Bo; Combs, Terry P.; Williams, Terence M.; Scherer, Philipp E.; Lisanti, Michael P.

doi:10.1152/ajpcell.00006.2003

Cited by 321 publications

(275 citation statements)

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“…This was correlated with increased expression of PI3K, PKB and p44/42 MAPK activity suggesting a regulatory role for Cav-1 in ozone-induced activation of these signaling pathways. Our findings are in accord with the observation that Cav-1 knockout mice exhibit hyperactivation of PI3K/PKB and p44/42 MAPK (Park et al, 2002;Cohen et al, 2003).…”

Section: Discussionsupporting

confidence: 92%

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Fakhrzadeh

Laskin²,

Laskin

2008

Toxicology and Applied Pharmacology

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Alveolar macrophages (AM) and inflammatory mediators including nitric oxide and peroxynitrite contribute to ozone-induced lung injury. The generation of these mediators is regulated, in part, by the transcription factor NF-κB. We previously demonstrated a critical role for NF-κB p50 in the ozone-induced injury. In the present studies mechanisms regulating NF-κB activation in the lung after ozone inhalation were analyzed. Treatment of wild type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-κB binding activity in AM, which persisted for at least 12 h. This was not evident in mice lacking TNFα which are protected from ozone-induced injury; there was also no evidence of nitric oxide or peroxynitrite production in lungs from these animals. These data demonstrate that TNFα plays a role in NF-κB activation and toxicity. TNFα signaling involves PI-3-kinase (PI3K)/protein kinase B (PKB), and p44/42 MAP kinase (MAPK) which are important in NF-κB activation. Ozone Inhalation resulted in rapid and transient increases in p44/42 MAPK and PI3K/PKB in AM from WT mice, which was evident immediately after exposure. Caveolin-1, a transmembrane protein that negatively regulates PI3K/PKB and p44/42 MAPK signaling, was downregulated in AM from WT mice after ozone exposure. In contrast, ozone had no effect on caveolin-1, PI3K/PKB or p44/42 MAPK expression in AM from TNFα knockout mice. These data, together with our findings that TNFα suppressed caveolin-1 in cultured AM, suggest that TNFα and downstream signaling mediate activation of NF-κB and the regulation of inflammatory genes important in ozone toxicity, and that this process is linked to caveolin-1.

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Section: Discussionsupporting

confidence: 92%

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Fakhrzadeh

Laskin²,

Laskin

2008

Toxicology and Applied Pharmacology

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“…Moreover, introduction of a modification of TC10 that prevents lipid raft association blocks the activation of the G protein by insulin, as well as the stimulation of glucose uptake in fat cells . Targeted disruption of the gene encoding the adipose-enriched raft protein caveolin1 also produced insulin resistance, although it remains uncertain whether this resulted from decreased insulin signaling (Cohen et al, 2003b). Taken together, these data suggest that lipid rafts serve as sites for assembly of signaling complexes that play an important role in insulin action.…”

Section: Discussionmentioning

confidence: 95%

Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

Inoue

Chiang

Chang

et al. 2006

MBoC

108

135

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Lipid raft microdomains act as organizing centers for signal transduction. We report here that the exocyst complex, consisting of Exo70, Sec6, and Sec8, regulates the compartmentalization of Glut4-containing vesicles at lipid raft domains in adipocytes. Exo70 is recruited by the G protein TC10 after activation by insulin and brings with it Sec6 and Sec8. Knockdowns of these proteins block insulin-stimulated glucose uptake. Moreover, their targeting to lipid rafts is required for glucose uptake and Glut4 docking at the plasma membrane. The assembly of this complex also requires the PDZ domain protein SAP97, a member of the MAGUKs family, which binds to Sec8 upon its translocation to the lipid raft. Exocyst assembly at lipid rafts sets up targeting sites for Glut4 vesicles, which transiently associate with these microdomains upon stimulation of cells with insulin. These results suggest that the TC10/exocyst complex/SAP97 axis plays an important role in the tethering of Glut4 vesicles to the plasma membrane in adipocytes. INTRODUCTIONInsulin stimulates glucose transport in fat and muscle cells through a process of regulated vesicle recycling in which the facilitative glucose transporter Glut4 is translocated from intracellular sites to the plasma membrane (Saltiel and Kahn, 2001;Bryant et al., 2002). In unstimulated cells, Glut4 undergoes endocytosis into endosomes and subsequently sorts into specialized storage vesicles that traffic to the plasma membrane after activation of the insulin receptor. The vesicles then dock and fuse at specific sites at the membrane, resulting in extracellular exposure of the transporter. The precise signals from the insulin receptor that control these events involve the tyrosine phosphorylation of a number of intracellular substrates. These phosphorylations lead to activation of the PI3-kinase pathway (Saltiel and Kahn, 2001) and also to activation of the G protein TC10 Maffucci et al., 2003), which in turn binds to numerous effectors, including the exocyst protein Exo70 (Inoue et al., 2003). Exo70 exists in a multiprotein complex with the proteins Sec6 and Sec8. A dominant-negative mutant of Exo70 blocked insulin-stimulated glucose uptake, but was without effect on translocation of Glut4 to the plasma membrane. However, this Exo70 mutant prevented the appearance of Glut4 at the cell surface, leading us to propose that the exocyst complex may play a critical role in tethering Glut4 vesicles to the plasma membrane for subsequent docking and fusion (Inoue et al., 2003).Lipid rafts are specialized compartments of the plasma membrane enriched in cholesterol and glycosphingolipids. Numerous signaling and cytoskeletal proteins are found in these subdomains, suggesting that they may act as organizing centers for signal transduction, particularly for insulin (Anderson, 1998;Schlegel et al., 1998;Bickel, 2002; Pessin, 2002, 2003). Both the insulin receptor and TC10 reside in lipid rafts (Yamamoto et al., 1998;Gustavsson et al., 1999;Nystrom et al., 1999;Kimura et al., 2002;Vainio et al., 2002)...

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“…Recent studies have suggested regulatory as well as structural functions for caveolin, which may directly regulate numerous signaling proteins in caveolae (Razani et al, 2002;Cohen et al, 2003b;Ha et al, 2003;Gratton et al, 2004;Kim et al, 2004;Kim and Pak, 2005). Different groups have demonstrated inhibition of G proteins, Src family kinases, nitric oxide synthase, epidermal growth factor receptor, MAP kinase, and protein kinase C by a caveolin scaffolding domain, leading to the suggestion that the biological function of caveolin in caveolae is to suppress cellular signaling (Uttenbogaard et al, 2000;Liu et al, 2002;Razani et al, 2002;Cohen et al, 2003b;Gratton et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Different groups have demonstrated inhibition of G proteins, Src family kinases, nitric oxide synthase, epidermal growth factor receptor, MAP kinase, and protein kinase C by a caveolin scaffolding domain, leading to the suggestion that the biological function of caveolin in caveolae is to suppress cellular signaling (Uttenbogaard et al, 2000;Liu et al, 2002;Razani et al, 2002;Cohen et al, 2003b;Gratton et al, 2004). The specificity of caveolin interaction with these molecules has been confirmed by identifying a common amino acid sequence motif contained in many of these regulatory molecules and in the insulin receptor (IR) as well (Cohen et al, 2003b;Gratton et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the caveolin-3 and Akt status in caveolae by insulin resistance in H9c2 cardiomyoblasts

Pak²

2005

Exp Mol Med

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Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue

Abstract: . Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue.

Cited by 321 publications

References 50 publications

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

Modulation of the caveolin-3 and Akt status in caveolae by insulin resistance in H9c2 cardiomyoblasts

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