Lipid Raft Targeting of the TC10 Amino Terminal Domain Is Responsible for Disruption of Adipocyte Cortical Actin

Hou, June Chunqiu; Pessin, Jeffrey E.

doi:10.1091/mbc.e03-01-0012

Cited by 28 publications

(10 citation statements)

References 79 publications

(66 reference statements)

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“…RHOQ also strongly differentiated VR-PAH from VN-PAH. This cytoskeletal gene facilitates protein transport and has been shown to be important in insulin-mediated signaling 29 , another pathway of importance in PAH 30–32 . Of note, only EPDR1, UCHL1, DSG2, SCD5 and P2RY5 expression levels were elevated in VR-PAH compared with VN-PAH, and gene expression levels were more commonly suppressed in VR-PAH which may reflect underlying disease mechanism.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension

et al. 2015

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Background Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than non-responsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular etiology from VN-PAH that can be detected in the peripheral blood. Methods and Results Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative PCR performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients based on the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors, cytoskeletal and rho/GTPase genes. 13/25 genes tested in whole blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2, TPD52, MKNL1, RAPGEF2 and PIAS1. Seven decision trees were built using expression levels of two genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ, which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5/5 VR-PAH in the validation cohort. Conclusions VR-PAH and VN-PAH can be differentiated using RNA expression patterns in peripheral blood. These differences may reflect different molecular etiologies of the two PAH phenotypes. This biomarker methodology may identify PAH patients that have a favorable treatment response.

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Section: Discussionmentioning

confidence: 99%

Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension

et al. 2015

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“…To test the effect of TC10 on the intracellular trafficking of CAL, we used confocal microscopy to examine the intracellular localization and distribution of CAL and TC10. Similar to H-ras, TC10 is synthesized by free ribosomes in the cytosol and then predominantly enters the conventional exocytic pathway from ER to Golgi en route to the plasma membrane (26,27). In transfected COS-7 cells, wild type HA-tagged TC10 is localized to the perinuclear secretory membrane compartments and the plasma membrane (Fig.…”

Section: Is the Expression Of Mature Cftr Proteinmentioning

confidence: 99%

“…The CAAX farnesylation motif is required for TC10 to enter the exocytic pathway from ER to Golgi. Upstream of CAAX sequence, a CXXC motif is found that functions in dual palmitoylation and plasma membrane targeting (26,27). Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, blocks farnesylation (28,29).…”

Section: Is the Expression Of Mature Cftr Proteinmentioning

confidence: 99%

Regulation of Cystic Fibrosis Transmembrane Regulator Trafficking and Protein Expression by a Rho Family Small GTPase TC10

Cheng

Wang

Guggino

2005

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR)-interacting protein, CFTR-associated ligand (CAL) down-regulates total and cell surface CFTR by targeting CFTR for degradation in the lysosome. Here, we report that a Rho family small GTPase TC10 interacts with CAL. This interaction specifically up-regulates CFTR protein expression. Co-expression of the constitutively active form, TC10Q75L, increases total and cell surface CFTR in a dose-dependent fashion. Moreover, co-expression of the dominant-negative mutant TC10T31N causes a dose-dependent reduction in mature CFTR. The effect of TC10 is independent of the level of CFTR expression, because a similar effect was observed in a stable cell line that expresses one-tenth of CFTR. Co-expression of TC10Q75L did not have a similar effect on the expression of plasma membrane proteins such as Frizzled-3 and Pr-cadherin or cytosolic proteins such as tubulin and green fluorescent protein. TC10Q75L also did not have a similar effect on the vesicular stomatitis virus glycoprotein. Co-expression of constitutively active and dominant-negative forms of Cdc42 or RhoA did not affect CFTR expression in a manner similar to TC10, indicating that the effect of TC10 is unique within the Rho family. Metabolic pulse-chase experiments show that TC10 did not affect CFTR maturation, suggesting that it exerts its effects on the mature CFTR. Importantly, TC10Q75L reverses CAL-mediated CFTR degradation, suggesting that TC10Q75L inhibits CAL-mediated degradation of CFTR. TC10Q75L does not operate by reducing CAL protein expression or its ability to form dimers or interact with CFTR. Interestingly, the expression of TC10Q75L causes a dramatic redistribution of CAL from the juxtanuclear region to the plasma membrane where the two molecules overlap. These data suggest that TC10 regulates both total and plasma membrane CFTR expression by interacting with CAL. The GTP-bound form of TC10 directs the trafficking of CFTR from the juxtanuclear region to the secretory pathway toward the plasma membrane, away from CAL-mediated degradation of CFTR in the lysosome.

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“…In 3T3-L1 adipocytes, overexpression of dominant-interfering TC10alpha mutant inhibits insulin-stimulated glucose uptake and GLUT4 translocation [ 82 , 89 ], suggesting the importance of GTPase activity in its function. On the contrary, another study shows that overexpression of TC10alpha or other chimeras with lipid raft-targeting motifs in adipocytes inhibits insulin-stimulated GLUT4 translocation, and these effects are independent of its GTPase activity but dependent on its membrane localization [ 90 ]. Furthermore, although siRNA-mediated TC10 knockdown was reported to effect insulin-simulated GLUT4 translocation, no other lab has reported the same findings and no mouse knockout models have corroborated these findings found in 3T3-L1 adipocytes.…”

Section: Temporal Regulators Of Insulin-stimulated Glut4 Translocamentioning

confidence: 99%

Spatiotemporal Regulators for Insulin-Stimulated GLUT4 Vesicle Exocytosis

Zhou

Shentu

2017

Journal of Diabetes Research

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Insulin increases glucose uptake and storage in muscle and adipose cells, which is accomplished through the mobilization of intracellular GLUT4 storage vesicles (GSVs) to the cell surface upon stimulation. Importantly, the dysfunction of insulin-regulated GLUT4 trafficking is strongly linked with peripheral insulin resistance and type 2 diabetes in human. The insulin signaling pathway, key signaling molecules involved, and precise trafficking itinerary of GSVs are largely identified. Understanding the interaction between insulin signaling molecules and key regulatory proteins that are involved in spatiotemporal regulation of GLUT4 vesicle exocytosis is of great importance to explain the pathogenesis of diabetes and may provide new potential therapeutic targets.

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Lipid Raft Targeting of the TC10 Amino Terminal Domain Is Responsible for Disruption of Adipocyte Cortical Actin

Cited by 28 publications

References 79 publications

Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension

Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension

Regulation of Cystic Fibrosis Transmembrane Regulator Trafficking and Protein Expression by a Rho Family Small GTPase TC10

Spatiotemporal Regulators for Insulin-Stimulated GLUT4 Vesicle Exocytosis

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