scholarly journals Phosphatidylinositol-3,4,5-Triphosphate and Cellular Signaling: Implications for Obesity and Diabetes

2015 ◽  
Vol 35 (4) ◽  
pp. 1253-1275 ◽  
Author(s):  
Prasenjit Manna ◽  
Sushil K. Jain
Keyword(s):  
Metabolic Diseases ◽  
Specific Binding ◽  
Cell Metabolism ◽  
Effector Proteins ◽  
Current Status ◽  
Cellular Functions ◽  
Binding Domains ◽  
Obesity And Diabetes ◽  
Impaired Metabolism ◽  
Wide Range

Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) is one of the most important phosphoinositides and is capable of activating a wide range of proteins through its interaction with their specific binding domains. Localization and activation of these effector proteins regulate a number of cellular functions, including cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. Phosphoinositides have been investigated as an important agonist-dependent second messenger in the regulation of diverse physiological events depending upon the phosphorylation status of their inositol group. Dysregulation in formation as well as metabolism of phosphoinositides is associated with various pathophysiological disorders such as inflammation, allergy, cardiovascular diseases, cancer, and metabolic diseases. Recent studies have demonstrated that the impaired metabolism of PtdIns(3,4,5)P3 is a prime mediator of insulin resistance associated with various metabolic diseases including obesity and diabetes. This review examines the current status of the role of PtdIns(3,4,5)P3 signaling in the regulation of various cellular functions and the implications of dysregulated PtdIns(3,4,5)P3 signaling in obesity, diabetes, and their associated complications.

scholarly journals The AAA+ ATPase p97, a cellular multitool

2017 ◽  
Vol 474 (17) ◽  
pp. 2953-2976 ◽  
Author(s):  
Lasse Stach ◽  
Paul S. Freemont
Keyword(s):  
Atp Hydrolysis ◽  
Current Status ◽  
Cellular Functions ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Binding Domains ◽  
Wide Range ◽  
Aaa Atpases ◽  
Substrate Proteins

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

scholarly journals The solution structure of pGolemi, a high affinity Mena EVH1 binding miniature protein, suggests explanations for paralog-specific binding to Ena/VASP homology (EVH) 1 domains

2009 ◽  
Vol 390 (5/6) ◽  
Author(s):  
Nina M. Link ◽  
Cornelia Hunke ◽  
Jonathan W. Mueller ◽  
Jutta Eichler ◽  
Peter Bayer
Keyword(s):  
Solution Structure ◽  
Specific Binding ◽  
Transmembrane Protein ◽  
Structural Data ◽  
Adaptor Proteins ◽  
Axonal Guidance ◽  
High Affinity ◽  
Binding Domains ◽  
Wide Range ◽  
Pancreatic Peptide

Abstract Ena/VASP homology 1 (EVH1) domains are polyproline binding domains that are present in a wide range of adaptor proteins, among them Ena/VASP proteins involved in actin remodeling and axonal guidance. The interaction of ActA, a transmembrane protein from the food-borne pathogen Listeria monocytogenes, with EVH1 domains has been shown to be crucial for recruitment of the host's actin skeleton and, as a consequence, for the infectivity of this bacterium. We present the structure of a synthetic high-affinity Mena EVH1 ligand, pGolemi, capable of paralog-specific binding, solved by NMR spectroscopy. This peptide shares the common pancreatic peptide fold with its scaffold, avian pancreatic peptide, but shows pivotal differences in the amino-terminus. The interplay of spatial fixation and flexibility appears to be the reason for its high affinity towards Mena EVH1. Combined with earlier investigations, our structural data shed light on the specificity determinants of pGolemi and the importance of additional binding epitopes around the residues Thr74 and Phe32 on EVH1 domains regulating paralog specificity. Our results are expected to facilitate the design of other high-affinity, paralog-specific EVH1 domain ligands, and serve as a fundament for the investigation of the molecular mode of action of EVH1 domains.

scholarly journals Thrombospondin 1 in Metabolic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda S. Gutierrez ◽  
Jovita Gutierrez
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Matricellular Protein ◽  
Published Data ◽  
Obesity And Diabetes ◽  
Thrombospondin 1 ◽  
Cancer And Inflammation

The thrombospondin family comprises of five multifunctional glycoproteins, whose best-studied member is thrombospondin 1 (TSP1). This matricellular protein is a potent antiangiogenic agent that inhibits endothelial migration and proliferation, and induces endothelial apoptosis. Studies have demonstrated a regulatory role of TSP1 in cell migration and in activation of the latent transforming growth factor beta 1 (TGFβ1). These functions of TSP1 translate into its broad modulation of immune processes. Further, imbalances in immune regulation have been increasingly linked to pathological conditions such as obesity and diabetes mellitus. While most studies in the past have focused on the role of TSP1 in cancer and inflammation, recently published data have revealed new insights about the role of TSP1 in physiological and metabolic disorders. Here, we highlight recent findings that associate TSP1 and its receptors to obesity, diabetes, and cardiovascular diseases. TSP1 regulates nitric oxide, activates latent TGFβ1, and interacts with receptors CD36 and CD47, to play an important role in cell metabolism. Thus, TSP1 and its major receptors may be considered a potential therapeutic target for metabolic diseases.

scholarly journals Potential Functions of the BMP Family in Bone, Obesity, and Glucose Metabolism

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yao Chen ◽  
Bingwei Ma ◽  
Xingchun Wang ◽  
Xiaojuan Zha ◽  
Chunjun Sheng ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Bone Metabolism ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Cellular Functions ◽  
Mineral Density ◽  
Pathophysiological Process ◽  
Obesity And Diabetes

Characteristic bone metabolism was observed in obesity and diabetes with controversial conclusions. Type 2 diabetes (T2DM) and obesity may manifest increased bone mineral density. Also, obesity is more easily to occur in T2DM. Therefore, we infer that some factors may be linked to bone and obesity as well as glucose metabolism, which regulate all of them. Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor- (TGF-) beta superfamily, regulate a diverse array of cellular functions during development and in the adult. More and more studies revealed that there exists a relationship between bone metabolism and obesity as well as glucose metabolism. BMP2, BMP4, BMP6, BMP7, and BMP9 have been shown to affect the pathophysiological process of obesity and glucose metabolism beyond bone metabolism. They may exert functions in adipogenesis and differentiation as well as insulin resistance. In the review, we summarize the literature on these BMPs and their association with metabolic diseases including obesity and diabetes.

scholarly journals Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1256
Author(s):  
Toufic Kassouf ◽  
Grzegorz Sumara
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Cell Metabolism ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Processes ◽  
Obesity And Diabetes ◽  
Extracellular Signal ◽  
Mediators Of Inflammation ◽  
Mitogen Activated Protein

The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.

Who does TORC2 talk to?

2018 ◽  
Vol 475 (10) ◽  
pp. 1721-1738 ◽  
Author(s):  
Jianling Xie ◽  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Gene Transcription ◽  
Cell Metabolism ◽  
Cellular Functions ◽  
Cellular Physiology ◽  
Cell Functions ◽  
Wide Range ◽  
And Control ◽  
Partner Proteins

The target of rapamycin (TOR) is a protein kinase that, by forming complexes with partner proteins, governs diverse cellular signalling networks to regulate a wide range of processes. TOR thus plays central roles in maintaining normal cellular functions and, when dysregulated, in diverse diseases. TOR forms two distinct types of multiprotein complexes (TOR complexes 1 and 2, TORC1 and TORC2). TORC1 and TORC2 differ in their composition, their control and their substrates, so that they play quite distinct roles in cellular physiology. Much effort has been focused on deciphering the detailed regulatory links within the TOR pathways and the structure and control of TOR complexes. In this review, we summarize recent advances in understanding mammalian (m) TORC2, its structure, its regulation, and its substrates, which link TORC2 signalling to the control of cell functions. It is now clear that TORC2 regulates several aspects of cell metabolism, including lipogenesis and glucose transport. It also regulates gene transcription, the cytoskeleton, and the activity of a subset of other protein kinases.

scholarly journals Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

2021 ◽  
Vol 9 ◽  
Author(s):  
Xue Jiang ◽  
Lianghui You ◽  
Zhenxing Zhang ◽  
Xianwei Cui ◽  
Hong Zhong ◽  
...  
Keyword(s):  
Breast Milk ◽  
Extracellular Vesicles ◽  
Messenger Rna ◽  
Metabolic Diseases ◽  
Biological Properties ◽  
Current Status ◽  
Physiological Functions ◽  
Obesity And Diabetes

Extracellular vesicles (EVs) are released by all cells under pathological and physiological conditions. EVs harbor various biomolecules, including protein, lipid, non-coding RNA, messenger RNA, and DNA. In 2007, mRNA and microRNA (miRNA) carried by EVs were found to have regulatory functions in recipient cells. The biological function of EVs has since then increasingly drawn interest. Breast milk, as the most important nutritional source for infants, contains EVs in large quantities. An increasing number of studies have provided the basis for the hypothesis associated with information transmission between mothers and infants via breast milk-derived EVs. Most studies on milk-derived EVs currently focus on miRNAs. Milk-derived EVs contain diverse miRNAs, which remain stable both in vivo and in vitro; as such, they can be absorbed across different species. Further studies have confirmed that miRNAs derived from milk-derived EVs can resist the acidic environment and enzymatic hydrolysis of the digestive tract; moreover, they can be absorbed by intestinal cells in infants to perform physiological functions. miRNAs derived from milk EVs have been reported in the maturation of immune cells, regulation of immune response, formation of neuronal synapses, and development of metabolic diseases such as obesity and diabetes. This article reviews current status and advances in milk-derived EVs, including their history, biogenesis, molecular contents, and biological functions. The effects of milk-derived EVs on growth and development in both infants and adults were emphasized. Finally, the potential application and future challenges of milk-derived EVs were discussed, providing comprehensive understanding and new insight into milk-derived EVs.

scholarly journals Species-specific secretion of ESX-5 type VII substrates is determined by the linker 2 of EccC5

2019 ◽  
Author(s):  
C. M. Bunduc ◽  
R. Ummels ◽  
W. Bitter ◽  
E.N.G. Houben
Keyword(s):  
Cell Envelope ◽  
Substrate Recognition ◽  
Effector Proteins ◽  
Specific Substrate ◽  
Secretion Systems ◽  
Binding Domains ◽  
Type Vii Secretion ◽  
Wide Range ◽  
Species Specific ◽  
System 1

AbstractType VII secretion systems (T7SSs) are used by mycobacteria to translocate a wide range of effector proteins across their diderm cell envelope. These systems, also known as ESX systems, have crucial roles for the viability and/or virulence of mycobacterial pathogens, including Mycobacterium tuberculosis and the fish pathogen Mycobacterium marinum. We previously observed species-specificity in the secretion of the PE_PGRS proteins by the ESX-5 system [1], in that the M. tuberculosis ESX-5 system was unable to fully complement an M. marinum esx-5 mutant. In this study, we established that the responsible factor for this is the central membrane ATPase EccC5, which has three nucleotide binding domains (NBDs). By creating chimeric M. marinum/M. tuberculosis EccC5 constructs, we observed that PE_PGRS secretion is mediated only in the presence of an EccC5 containing the cognate linker 2, irrespective of the origin of the EccC5 backbone. This region is responsible for linking the first two NBDs and for keeping the first NBD in an inhibited state. Notably, this region is disordered in a EccC crystal structure and is particularly extended in EccC proteins of the different ESX-5 systems. These results indicate that this region is involved in species-specific substrate recognition and might therefore be an additional substrate recognition site of EccC5.

scholarly journals The P. aeruginosa Type VI Secretion System Effector Tse5 Forms Ion-Selective Membrane Pores that Disrupt the Membrane Potential of Intoxicated Cells

2021 ◽  
Author(s):  
Amaia González-Magaña ◽  
Jon Altuna ◽  
María Queralt-Martín ◽  
Eneko Largo ◽  
Itxaso Montánchez ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Type Vi Secretion System ◽  
Cellular Functions ◽  
Fitness Advantage ◽  
Type Vi Secretion ◽  
Wide Range ◽  
Membrane Depolarisation

Abstract The Type VI Secretion System (T6SS) of Pseudomonas aeruginosa injects effector proteins into neighbouring competitors and host cells, providing a fitness advantage that allows this opportunistic nosocomial pathogen to persist and prevail during the onset of infections. However, despite the high clinical relevance of P. aeruginosa, the identity and mode of action of most P. aeruginosa T6SS-dependent effectors remain to be discovered. Here, we report the molecular mechanism of Tse5-CT, which is the toxic auto-proteolytic product of the P. aeruginosa T6SS exported effector Tse5. Our results demonstrate Tse5-CT is a pore-forming toxin that can transport ions across the membrane, causing membrane depolarisation and bacterial death. The membrane potential regulates a wide range of essential cellular functions, and therefore membrane depolarisation is an efficient strategy to compete with other microorganisms in polymicrobial environments.

scholarly journals Sirtuins and their role as physiological modulators of metabolism

2020 ◽  
Vol 74 ◽  
pp. 489-497
Author(s):  
Grażyna Sygitowicz ◽  
Dariusz Sitkiewicz
Keyword(s):  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Acid Oxidation ◽  
Special Role ◽  
Cellular Functions ◽  
Current State ◽  
Expression Of Genes ◽  
Wide Range ◽  
Adp Ribosyltransferase

The sirtuins are a family of highly evolutionary conserved NAD+-dependent deacetylases (SIRT1, 2, 3, 5). Certain human sirtuins (SIRT4, 6) have, in addition, an ADP-ribosyltransferase activity. SIRT1 and SIRT2 are located in the nucleus and cytoplasm; SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. The mammalian sirtuins have emerged as key metabolic sensors that directly link environmental nutrient signals to metabolic homeostasis. SIRT1 is involved in the regulation of gluconeogenesis and fatty acid oxidation, as well as inhibiting lipogenesis and inflammation in the liver. In addition, they contribute to the mobilization of fat in white adipose tissue, sense nutrient availability in the hypothalamus; regulate insulin secretion in the pancreas; as well as modulating the expression of genes responsible for the activity of the circadian clock in metabolic tissues. Sirtuins are implicated in a variety of cellular functions ranging from gene silencing, through the control of the cell cycle, to energy homeostasis. Caloric restriction, supported by polyphenols, including resveratrol, which is the SIRT1 activator, plays a special role in maintaining energy homeostasis. On a whole body level, the wide range of cellular activities of the sirtuins suggests that they could constitute a therapeutic target to combat obesity and related metabolic diseases. In addition, this work presents the current state of knowledge in the field of sirtuin activity in relation to nutritional status and lifespan.

Sign in / Sign up

Export Citation Format

Share Document