Scaffolding protein IQGAP1: an insulin-dependent link between caveolae and the cytoskeleton in primary human adipocytes?

2016 ◽  
Vol 473 (19) ◽  
pp. 3177-3188 ◽  
Author(s):  
Åsa Jufvas ◽  
Meenu R. Rajan ◽  
Cecilia Jönsson ◽  
Peter Strålfors ◽  
Maria V. Turkina
Keyword(s):  
Cytoskeletal Proteins ◽  
Scaffolding Protein ◽  
Proximity Ligation Assay ◽  
Human Adipocytes ◽  
Cellular Functions ◽  
Iq Motif ◽  
Caveolin 1 ◽  
Nondiabetic Control ◽  
Cytoskeletal Elements

The ubiquitously expressed IQ motif-containing GTPase activating protein-1 (IQGAP1) is a scaffolding protein implicated in an array of cellular functions, in particular by binding to cytoskeletal elements and signaling proteins. A role of IQGAP1 in adipocytes has not been reported. We therefore investigated the cellular IQGAP1 interactome in primary human adipocytes. Immunoprecipitation and quantitative mass spectrometry identified caveolae and caveolae-associated proteins as the major IQGAP1 interactors alongside cytoskeletal proteins. We confirmed co-localization of IQGAP1 with the defining caveolar marker protein caveolin-1 by confocal microscopy and proximity ligation assay. Most interestingly, insulin enhanced the number of IQGAP1 interactions with caveolin-1 by five-fold. Moreover, we found a significantly reduced abundance of IQGAP1 in adipocytes from patients with type 2 diabetes compared with cells from nondiabetic control subjects. Both the abundance of IQGAP1 protein and mRNA were reduced, indicating a transcriptional defect in diabetes. Our findings suggest a novel role of IQGAP1 in insulin-regulated interaction between caveolae and cytoskeletal elements of the adipocyte, and that this is quelled in the diabetic state.

Abstract 16629: Endothelial Caveolin-1-trpv4 Regulation of Pulmonary Arterial Pressure and Impairment in Pulmonary Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
YEN LIN CHEN ◽  
Kwangseok Hong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Mouse Models ◽  
Pulmonary Arterial Pressure ◽  
Scaffolding Protein ◽  
Channel Activity ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Background: Pulmonary hypertension (PH) is a degenerative disorder that is characterized by elevated vascular resistance and pulmonary arterial pressure (PAP). Endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels represent an important Ca 2+ influx signaling mechanism that promotes vasodilation of small pulmonary arteries (PAs). Scaffolding protein caveolin-1 (Cav-1) has been shown to precipitate with TRPV4 channels in pulmonary endothelial cells in culture. Hypothesis: We hypothesized that the endothelial Cav-1-TRPV4 channel signaling in small PAs lowers PAP, and is impaired in PH. Methods: Inducible endothelium-specific KO mice for TRPV4 channel or Cav-1 were used to study the role of Cav-1-TRPV4 signaling in the regulation of resting PAP. Endothelium-specific P2Y2 receptor KO mice were used to test if Cav-1 provides a signaling scaffold for purinergic activation of TRPV4 EC channels. Endothelial Cav-1-TRPV4 signaling was assessed in PAs from two PH mouse models and PH patients. The role of NADPH oxidase (NOX1)- and inducible nitric oxide synthase (iNOS)-mediated peroxynitrite (PN), an oxidant molecule, in impairing Cav-1-TRPV4 signaling in PH was evaluated using NOX1-/- and iNOS-/- mice and pharmacological inhibitors. Results: We show that endothelial Cav-1-TRPV4 signaling in small PAs lowers resting PAP, and protects against the pathogenesis of PH. Endothelial Cav-1 provides a signaling scaffold for the activation of TRPV4 channels by endogenous purinergic receptor signaling. Moreover, TRPV4 EC channel activity and Cav-1-TRPV4 signaling are impaired in small PAs from two mouse models of PH and PH patients. Elevated levels of NOX1 and iNOS enzymes in caveolae resulted in PN formation close to Cav-1 in PH. Elevated PN targeted Cav-1 to lower Cav-1-TRPV4 signaling, thereby contributing to impaired vasodilation and increased PAP. Pharmacological inhibition of NOX1, iNOS, or PN rescued TRPV4 EC channel activity and vasodilation in PH. Conclusion: This study provides novel evidence that endothelial Cav-1-TRPV4 signaling lowers PAP and is impaired in PH. Inhibiting NOX1 or iNOS activity, or lowering endothelial PN levels may represent a novel strategy for restoring TRPV4 EC channel activity, vasodilation, and PAP.

scholarly journals Caveolin-1 stabilizes ATP7A, a copper transporter for extracellular SOD, in vascular tissue to maintain endothelial function

2020 ◽  
Vol 319 (5) ◽  
pp. C933-C944
Author(s):  
Varadarajan Sudhahar ◽  
Mustafa Nazir Okur ◽  
John P. O’Bryan ◽  
Richard D. Minshall ◽  
David Fulton ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Lipid Rafts ◽  
Vascular Tissue ◽  
Proteasomal Degradation ◽  
Scaffolding Protein ◽  
Copper Transporter ◽  
Caveolin 1

Caveolin-1 (Cav-1) is a scaffolding protein and a major component of caveolae/lipid rafts. Previous reports have shown that endothelial dysfunction in Cav-1-deficient (Cav-1−/−) mice is mediated by elevated oxidative stress through endothelial nitric oxide synthase (eNOS) uncoupling and increased NADPH oxidase. Oxidant stress is the net balance of oxidant generation and scavenging, and the role of Cav-1 as a regulator of antioxidant enzymes in vascular tissue is poorly understood. Extracellular SOD (SOD3) is a copper (Cu)-containing enzyme that is secreted from vascular smooth muscle cells/fibroblasts and subsequently binds to the endothelial cells surface, where it scavenges extracellular [Formula: see text] and preserves endothelial function. SOD3 activity is dependent on Cu, supplied by the Cu transporter ATP7A, but whether Cav-1 regulates the ATP7A-SOD3 axis and its role in oxidative stress-mediated vascular dysfunction has not been studied. Here we show that the activity of SOD3, but not SOD1, was significantly decreased in Cav-1−/− vessels, which was rescued by re-expression of Cav-1 or Cu supplementation. Loss of Cav-1 reduced ATP7A protein, but not mRNA, and this was mediated by ubiquitination of ATP7A and proteasomal degradation. ATP7A bound to Cav-1 and was colocalized with SOD3 in caveolae/lipid rafts or perinucleus in vascular tissues or cells. Impaired endothelium-dependent vasorelaxation in Cav-1−/− mice was rescued by gene transfer of SOD3 or by ATP7A-overexpressing transgenic mice. These data reveal an unexpected role of Cav-1 in stabilizing ATP7A protein expression by preventing its ubiquitination and proteasomal degradation, thereby increasing SOD3 activity, which in turn protects against vascular oxidative stress-mediated endothelial dysfunction.

Postsynaptic nanodomains generated by local palmitoylation cycles

2015 ◽  
Vol 43 (2) ◽  
pp. 199-204 ◽  
Author(s):  
Masaki Fukata ◽  
Atsushi Sekiya ◽  
Tatsuro Murakami ◽  
Norihiko Yokoi ◽  
Yuko Fukata
Keyword(s):  
Plasma Membrane ◽  
Protein Targeting ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Membrane Domains ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Protein Palmitoylation ◽  
Specific Proteins

Precise regulation of protein assembly at specialized membrane domains is essential for diverse cellular functions including synaptic transmission. However, it is incompletely understood how protein clustering at the plasma membrane is initiated, maintained and controlled. Protein palmitoylation, a common post-translational modification, regulates protein targeting to the plasma membrane. Such modified proteins are enriched in these specialized membrane domains. In this review, we focus on palmitoylation of PSD-95, which is a major postsynaptic scaffolding protein and makes discrete postsynaptic nanodomains in a palmitoylation-dependent manner and discuss a determinant role of local palmitoylation cycles in creating highly localized hotspots at the membrane where specific proteins concentrate to organize functional domains.

Role of caveolin-1 and cytoskeletal proteins, actin and vimentin, in adipogenesis of bovine intramuscular preadipocyte cells

2004 ◽  
Vol 28 (8-9) ◽  
pp. 615-623 ◽  
Author(s):  
T TAKENOUCHI ◽  
N MIYASHITA ◽  
K OZUTSUMI ◽  
M ROSE ◽  
H ASO
Keyword(s):  
Cytoskeletal Proteins ◽  
Caveolin 1

scholarly journals Cytoskeleton of Apicomplexan Parasites

2002 ◽  
Vol 66 (1) ◽  
pp. 21-38 ◽  
Author(s):  
Naomi S. Morrissette ◽  
L. David Sibley
Keyword(s):  
Cytoskeletal Proteins ◽  
Opportunistic Pathogens ◽  
Protozoan Parasites ◽  
Apicomplexan Parasites ◽  
Obligate Intracellular ◽  
Intracellular Parasites ◽  
Eimeria Spp ◽  
Cytoskeletal Elements ◽  
Theileria Spp

SUMMARY The Apicomplexa are a phylum of diverse obligate intracellular parasites including Plasmodium spp., the cause of malaria; Toxoplasma gondii and Cryptosporidium parvum, opportunistic pathogens of immunocompromised individuals; and Eimeria spp. and Theileria spp., parasites of considerable agricultural importance. These protozoan parasites share distinctive morphological features, cytoskeletal organization, and modes of replication, motility, and invasion. This review summarizes our current understanding of the cytoskeletal elements, the properties of cytoskeletal proteins, and the role of the cytoskeleton in polarity, motility, invasion, and replication. We discuss the unusual properties of actin and myosin in the Apicomplexa, the highly stereotyped microtubule populations in apicomplexans, and a network of recently discovered novel intermediate filament-like elements in these parasites.

scholarly journals Microtubules: Evolving roles and critical cellular interactions

2019 ◽  
Vol 244 (15) ◽  
pp. 1240-1254 ◽  
Author(s):  
Caitlin M Logan ◽  
A Sue Menko
Keyword(s):  
Cytoskeletal Proteins ◽  
Cellular Interactions ◽  
Post Translational Modifications ◽  
Microtubule Stabilization ◽  
Directed Cell Migration ◽  
Organelle Trafficking ◽  
New Research ◽  
Cytoskeletal Elements ◽  
Shed Light

Microtubules are cytoskeletal elements known as drivers of directed cell migration, vesicle and organelle trafficking, and mitosis. In this review, we discuss new research in the lens that has shed light into further roles for stable microtubules in the process of development and morphogenesis. In the lens, as well as other systems, distinct roles for characteristically dynamic microtubules and stabilized populations are coming to light. Understanding the mechanisms of microtubule stabilization and the associated microtubule post-translational modifications is an evolving field of study. Appropriate cellular homeostasis relies on not only one cytoskeletal element, but also rather an interaction between cytoskeletal proteins as well as other cellular regulators. Microtubules are key integrators with actin and intermediate filaments, as well as cell–cell junctional proteins and other cellular regulators including myosin and RhoGTPases to maintain this balance. Impact statement The role of microtubules in cellular functioning is constantly expanding. In this review, we examine new and exciting fields of discovery for microtubule’s involvement in morphogenesis, highlight our evolving understanding of differential roles for stabilized versus dynamic subpopulations, and further understanding of microtubules as a cellular integrator.

scholarly journals Cell-Specific Dual Role of Caveolin-1 in Pulmonary Hypertension

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Rajamma Mathew
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Dual Role ◽  
Scaffolding Protein ◽  
Suppressor Factor ◽  
Caveolin 1 ◽  
Enhanced Expression

A wide variety of cardiopulmonary and systemic diseases are known to lead to pulmonary hypertension (PH). A number of signaling pathways have been implicated in PH; however, the precise mechanism/s leading to PH is not yet clearly understood. Caveolin-1, a membrane scaffolding protein found in a number of cells including endothelial and smooth muscle cells, has been implicated in PH. Loss of endothelial caveolin-1 is reported in clinical and experimental forms of PH. Caveolin-1, also known as a tumor-suppressor factor, interacts with a number of transducing molecules that reside in or are recruited to caveolae, and it inhibits cell proliferative pathways. Not surprisingly, the rescue of endothelial caveolin-1 has been found not only to inhibit the activation of proliferative pathways but also to attenuate PH. Recently, it has emerged that during the progression of PH, enhanced expression of caveolin-1 occurs in smooth muscle cells, where it facilitates cell proliferation, thus contributing to worsening of the disease. This paper summarizes the cell-specific dual role of caveolin-1 in PH.

scholarly journals Differences in the expression of caveolin-1 isoforms in cancer-associated and normal fibroblasts of patients with oral squamous cell carcinoma

2021 ◽  
Author(s):  
S. Kaya ◽  
Nadine Wiesmann ◽  
J. Goldschmitt ◽  
M. Krüger ◽  
B. Al-Nawas ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Tumor Progression ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Scaffolding Protein ◽  
Caveolin 1 ◽  
Tumor Stages

Abstract Objectives For many years, tumor development has been viewed as a cell-autonomous process; however, today we know that the tumor microenvironment (TME) and especially cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression. Caveolin-1 (Cav-1) is a scaffolding protein which is involved in several cancer-associated processes as important component of the caveolae. Our goal was to shed light on the expression of the two different isoforms of Cav-1 in normal fibroblasts (NFs) and CAFs of patients with oral squamous cell carcinoma (OSCC). Materials and methods Fibroblasts from normal mucosa and CAFs were isolated and propagated in vitro. Gene expression of the different Cav-1 isoforms was assessed via quantitative real-time PCR (qPCR) and supplemented by protein expression analysis. Results We could show that the Cav-1β isoform is more highly expressed in NFs and CAFs compared to Cav-1α. Furthermore, the different Cav-1 isoforms tended to be differently expressed in different tumor stages. However, this trend could not be seen consistently, which is in line with the ambiguous role of Cav-1 in tumor progression described in literature. Western blotting furthermore revealed that NFs and CAFs might differ in the oligomerization profile of the Cav-1 protein. Conclusion These differences in expression of Cav-1 between NFs and CAFs of patients with OSCC confirm that the protein might play a role in tumor progression and is of interest for further analyses. Clinical relevance Our findings support a possible role of the two isoforms of Cav-1 in the malignant transformation of OSCC.

scholarly journals Caveolin-1: a critical regulator of lung injury

2011 ◽  
Vol 300 (2) ◽  
pp. L151-L160 ◽  
Author(s):  
Yang Jin ◽  
Seon-Jin Lee ◽  
Richard D. Minshall ◽  
Augustine M. K. Choi
Keyword(s):  
Lung Injury ◽  
Severe Form ◽  
Therapeutic Interventions ◽  
Scaffolding Protein ◽  
Type I ◽  
Cellular Functions ◽  
Cellular Mechanisms ◽  
Caveolin 1 ◽  
Cell Functions ◽  
And Function

Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Cav-1 regulates critical cell functions including proliferation, apoptosis, cell differentiation, and transcytosis via diverse signaling pathways. Abundant in almost every cell type in the lung, including type I epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, macrophages, and neutrophils, cav-1 plays a crucial role in the pathogenesis of acute lung injury (ALI). ALI and its severe form, acute respiratory distress syndrome (ARDS), are responsible for significant morbidity and mortality in intensive care units, despite improvement in ventilation strategies. The pathogenesis of ARDS is still poorly understood, and therapeutic options remain limited. In this article, we summarize recent data regarding the regulation and function of cav-1 in lung biology and pathology, in particular as it relates to ALI. We further discuss the potential molecular and cellular mechanisms by which cav-1 expression contributes to ALI. Investigating the cellular functions of cav-1 may provide new insights for understanding the pathogenesis of ALI and provide novel targets for therapeutic interventions in the future.

scholarly journals Role of Caveolin-1 in Diabetes and Its Complications

2020 ◽  
Vol 2020 ◽  
pp. 1-20 ◽  
Author(s):  
Dania Haddad ◽  
Ashraf Al Madhoun ◽  
Rasheeba Nizam ◽  
Fahd Al-Mulla
Keyword(s):  
Insulin Resistance ◽  
Signal Transduction ◽  
Insulin Secretion ◽  
Recent Progress ◽  
Principal Component ◽  
Integral Membrane Protein ◽  
Cholesterol Homeostasis ◽  
Cellular Functions ◽  
Caveolin 1

It is estimated that in 2017 there were 451 million people with diabetes worldwide. These figures are expected to increase to 693 million by 2045; thus, innovative preventative programs and treatments are a necessity to fight this escalating pandemic disorder. Caveolin-1 (CAV1), an integral membrane protein, is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance. Here, we summarize the recent progress on the role of CAV1 in diabetes and diabetic complications.

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