Institute Investigacion Sanitaria La Princesa

Madrid, Spain

Institute Investigacion Sanitaria La Princesa

Madrid, Spain
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Fernandez-Veledo S.,Rovira i Virgili University | Fernandez-Veledo S.,CIBER ISCIII | Vazquez-Carballo A.,Complutense University of Madrid | Vila-Bedmar R.,Institute Investigacion Sanitaria la Princesa | And 4 more authors.
IUBMB Life | Year: 2013

Recent advances have demonstrated that the adipose tissue plays a central role in regulating overall energy balance. Obesity results from a chronic deregulation of energy balance, with energy intake exceeding energy expenditure. Recently, new mechanisms that control the obesity phenotype such as the equilibrium between white and brown adipose tissue function has been identified. In this context, it is becoming increasingly clear that in addition to cellular growth, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) also regulate lipid metabolism and adipogenesis. Here, we review recent advances in the understanding of the molecular mechanisms involved in white and brown differentiation programs focusing on AMPK and mTOR signaling pathways, which may play differential roles in white adipose tissue and brown adipose tissue development. In view of the worldwide epidemic of obesity and its associated metabolic disorders such as insulin resistance and type 2 diabetes, targeting these kinases may represent a potential approach for reducing adiposity and improving obesity-related diseases. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

Vila-Bedmar R.,Institute Investigacion Sanitaria la Princesa | Murga C.,Institute Investigacion Sanitaria la Princesa | VanHook A.M.,Web Editor
Science Signaling | Year: 2015

This Podcast features an interview with Cristina Murga and Rocio Vila-Bedmar, authors of a Research Article that appears in the 21 July 2015 issue of Science Signaling, about how deleting the kinase GRK2 can counteract some of the metabolic effects of a bad diet. Obesity affects many of the body's normal functions, most notably metabolism. Obesity is associated with insulin resistance and reduced glucose tolerance, which can lead to type 2 diabetes. It also promotes hepatic steatosis, the accumulation of fat in the liver. Vila-Bedmar et al. show that deleting GRK2 can prevent further weight gain and hepatic steatosis and improve glucose sensitivity in obese mice. Deleting GRK2 improved these metabolic consequences of high-fat diet-induced obesity even if the kinase was deleted after the mice had already become obese and resistant to insulin. © 2015 American Association for the Advancement of Science. All rights Reserved.

Vila-Bedmar R.,Institute Investigacion Sanitaria la Princesa | Cruces-Sande M.,Institute Investigacion Sanitaria la Princesa | Lucas E.,Institute Investigacion Sanitaria la Princesa | Willemen H.L.D.M.,University Utrecht | And 6 more authors.
Science Signaling | Year: 2015

Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide - binding protein) - coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet - dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity. Copyright 2015 by the American Association for the Advancement of Science.

PubMed | Rovira i Virgili University, University of Navarra, Temple University and Institute Investigacion Sanitaria La Princesa
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2014

G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2(+/-) mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.

Lafarga V.,Autonomous University of Madrid | Lafarga V.,Institute Investigacion Sanitaria la Princesa | Aymerich I.,Autonomous University of Madrid | Tapia O.,University of Cantabria | And 4 more authors.
EMBO Journal | Year: 2012

Cell motility and adhesion involves dynamic microtubule (MT) acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major cytoplasmic α-tubulin deacetylase. We identify G protein-coupled receptor kinase 2 (GRK2) as a key novel stimulator of HDAC6. GRK2, which levels inversely correlate with the extent of α-tubulin acetylation in epithelial cells and fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate α-tubulin deacetylase activity. Remarkably, phosphorylation of GRK2 itself at S670 specifically potentiates its ability to regulate HDAC6. GRK2 and HDAC6 colocalize in the lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced motility. Consistently, cells expressing GRK2-K220R or GRK2-S670A mutants, unable to phosphorylate HDAC6, exhibit highly acetylated cortical MTs and display impaired migration and protrusive activity. Finally, we find that a balanced, GRK2/HDAC6-mediated regulation of tubulin acetylation differentially modulates the early and late stages of cellular spreading. This novel GRK2/HDAC6 functional interaction may have important implications in pathological contexts. © 2012 European Molecular Biology Organization | All Rights Reserved.

Penela P.,Autonomous University of Madrid | Penela P.,Institute Investigacion Sanitaria La Princesa | Lafarga V.,Autonomous University of Madrid | Lafarga V.,Institute Investigacion Sanitaria La Princesa | And 13 more authors.
Science Signaling | Year: 2012

G protein-coupled receptor kinase 2 (GR K2) is a ubiquitous, essential protein kinase that is emerging as an integrative node in many signaling networks. Moreover, changes in GR K2 abundance and activity have been identified in several inflammatory, cardiovascular disease, and tumor contexts, suggesting that those alterations may contribute to the initiation or development of pathologies. GR Ks were initially identified as key players in the desensitization and internalization of multiple G protein-coupled receptors (GPCR s), but GR K2 also phosphorylates several non-GPCR substrates and dynamically associates with a variety of proteins related to signal transduction. Ongoing research in our laboratory is aimed at understanding how specific GRK2 interactomes are orchestrated in a stimulus-, context-, or cell type-specific manner. We have recently identified an interaction between GRK2 and histone deacetylase 6 (HDAC6) that modulates cell spreading and motility. HDAC6 is a major cytoplasmic α-tubulin deacetylase that is involved in cell motility and adhesion. GRK2 dynamically and directly associates with and phosphorylates HDAC6 to stimulate its α-tubulin deacetylase activity at specific cellular localizations, such as the leading edge of migrating cells, thus promoting local tubulin deacetylation and enhanced motility. GRK2-HDAC6-mediated regulation of tubulin acetylation also modulates cellular spreading. This GRK2-HDAC6 functional interaction may have important implications in pathological contexts related to epithelial cell migration.

Fernandez-Arenas E.,Autonomous University of Madrid | Calleja E.,Autonomous University of Madrid | Martinez-Martin N.,Autonomous University of Madrid | Gharbi S.I.,CSIC - National Center for Biotechnology | And 9 more authors.
EMBO Journal | Year: 2014

T-cell receptors (TCR) recognize their antigen ligand at the interface between T cells and antigen-presenting cells, known as the immunological synapse (IS). The IS provides a means of sustaining the TCR signal which requires the continual supply of new TCRs. These are endocytosed and redirected from distal membrane locations to the IS. In our search for novel cytoplasmic effectors, we have identified β-arrestin-1 as a ligand of non-phosphorylated resting TCRs. Using dominant-negative and knockdown approaches we demonstrate that β-arrestin-1 is required for the internalization and downregulation of non-engaged bystander TCRs. Furthermore, TCR triggering provokes the β-arrestin-1-mediated downregulation of the G-protein coupled chemokine receptor CXCR4, but not of other control receptors. We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163. This mechanism allows the first triggered TCRs to deliver a stop migration signal, and to promote the internalization of distal TCRs and CXCR4 and their translocation to the IS. This receptor crosstalk mechanism is critical to sustain the TCR signal. Synopsis Activated T-cell receptors (TCRs) employ β-arrestin-mediated internalization to downregulate migratory chemokine receptors, but surprisingly also to recruit unliganded peripheral TCRs to the immunological synapse. β-arrestin-1 binds non-phosphorylated tyrosine containing motifs, ITAMs, of the TCR. TCR triggering stimulates the phosphorylation by PKC of Ser163 in the phosphate sensor sequence of β-arrestin-1. Ser163 phosphorylation is required for β-arrestin-1 recruitment to the TCR. β-arrestin-1 is required for the TCR triggered downregulation of bystander TCRs and CXCR4. β-arrestin-1-mediated downregulation of distal TCRs allows the immunological synapse to be fed with new TCRs and to sustain the TCR signal. Activated T-cell receptors (TCRs) employ β-arrestin-mediated internalization to downregulate migratory chemokine receptors, but surprisingly also to recruit unliganded peripheral TCRs to the immunological synapse. © 2014 The Authors.

Penela P.,Autonomous University of Madrid | Penela P.,Institute Investigacion Sanitaria La Princesa | Nogues L.,Autonomous University of Madrid | Nogues L.,Institute Investigacion Sanitaria La Princesa | And 2 more authors.
Current Opinion in Cell Biology | Year: 2014

G protein-coupled receptor kinases (GRKs) are emerging as important integrative nodes in cell migration processes. Recent evidence links GRKs (particularly the GRK2 isoform) to the complex modulation of diverse aspects of cell motility. In addition to its well-established role in the desensitization of G protein-coupled receptors involved in chemotaxis, GRK2 can play an effector role in the organization of actin and microtubule networks and in adhesion dynamics, by means of novel substrates and transient interacting partners, such as the GIT1 scaffold or the cytoplasmic α-tubulin deacetylase histone deacetylase 6 (HDAC6). The overall effect of altering GRK levels or activity on chemotaxis would depend on how such different roles are integrated in a given cell type and physiological context, and may have relevant implications in inflammatory diseases or cancer progression. © 2013 Elsevier Ltd.

Sanchez-Fernandez G.,Autonomous University of Madrid | Sanchez-Fernandez G.,Institute Investigacion Sanitaria La Princesa | Cabezudo S.,Autonomous University of Madrid | Cabezudo S.,Institute Investigacion Sanitaria La Princesa | And 8 more authors.
Cellular Signalling | Year: 2014

In the last few years the interactome of Gαq has expanded considerably, contributing to improve our understanding of the cellular and physiological events controlled by this G alpha subunit. The availability of high-resolution crystal structures has led the identification of an effector-binding region within the surface of Gαq that is able to recognise a variety of effector proteins. Consequently, it has been possible to ascribe different Gαq functions to specific cellular players and to identify important processes that are triggered independently of the canonical activation of phospholipase Cβ (PLCβ), the first identified Gαq effector. Novel effectors include p63RhoGEF, that provides a link between G protein-coupled receptors and RhoA activation, phosphatidylinositol 3-kinase (PI3K), implicated in the regulation of the Akt pathway, or the cold-activated TRPM8 channel, which is directly inhibited upon Gαq binding. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has also been described as a novel PLCβ-independent signalling axis that relies upon the interaction between this G protein and two novel effectors (PKCφ and MEK5). Additionally, the association of Gαq with different regulatory proteins can modulate its effector coupling ability and, therefore, its signalling potential. Regulators include accessory proteins that facilitate effector activation or, alternatively, inhibitory proteins that downregulate effector binding or promote signal termination. Moreover, Gαq is known to interact with several components of the cytoskeleton as well as with important organisers of membrane microdomains, which suggests that efficient signalling complexes might be confined to specific subcellular environments. Overall, the complex interaction network of Gαq underlies an ever-expanding functional diversity that puts forward this G alpha subunit as a major player in the control of physiological functions and in the development of different pathological situations. © 2014 Elsevier Inc.

Casafont I.,University of Cantabria | Palanca A.,University of Cantabria | Lafarga V.,Autonomous University of Madrid | Lafarga V.,Institute Investigacion Sanitaria la Princesa | And 2 more authors.
Acta Neuropathologica | Year: 2011

Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0-G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons. © 2011 Springer-Verlag.

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