The role of endocytosis in activating and regulating signal transduction

Endocytosis is increasingly understood to play crucial roles in most signaling pathways, from determining which signaling components are activated, to how the signal is subsequently transduced and/or terminated. Whether a receptor-ligand complex is internalized via a clathrin-dependent or clathrin-independent endocytic route, and the complexes' subsequent trafficking through specific endocytic compartments, to then be recycled or degraded, has profound effects on signaling output. This review discusses the roles of endocytosis in three markedly different signaling pathways: the Wnt, Notch, and Eph/Ephrin pathways. These offer fundamentally different signaling systems: (1) diffusible ligands inducing signaling in one cell, (2) membrane-tethered ligands inducing signaling in a contacting receptor cell, and (3) bi-directional receptor-ligand signaling in two contacting cells. In each of these systems, endocytosis controls signaling in fascinating ways, and comparison of their similarities and dissimilarities will help to expand our understanding of endocytic control of signal transduction across multiple signaling pathways.     

Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes

Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy.     

Neuronal ciliary signaling in homeostasis and disease

Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.     

Endoplasmic reticulum stress responses

In homeostasis, cellular processes are in a dynamic equilibrium. Perturbation of homeostasis causes stress. In this review I summarize how perturbation of three major functions of the endoplasmic reticulum (ER) in eukaryotic cells–protein folding, lipid and sterol biosynthesis, and storing intracellular Ca²⁺ – causes ER stress and activates signaling pathways collectively termed the unfolded protein response (UPR). I discuss how the UPR reestablishes homeostasis, and summarize our current understanding of how the transition from protective to apoptotic UPR signaling is controlled, and how the UPR induces inflammatory signaling. Received 21 August 2007; received after revision 26 October 2007; accepted 29 October 2007     

Lysosomal multienzyme complex: pros and cons of working together

The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this ‘core’ complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.     

Development and differentiation of the intestinal epithelium

The gastrointestinal tract develops from a simple tube to a complex organ with patterns of differentiation along four axes of asymmetry. The organ is composed of all three germ layers signaling to each other during development to form the adult structure. The gut epithelium is a constitutively developing tissue, constantly differentiating from a stem cell in a progenitor pool throughout the life of the organism. Signals from the adjacent mesoderm and between epithelial cells are required for normal orderly development/differentiation, homeostasis, and apoptosis. Embryonically important patterning factors are used during adult stages for these processes. Such critical pathways as the hedgehog, bone morphogenetic protein, Notch, Sox, and Wnt systems are used both in embryologic and adult times of gut development. We focus on and review the roles of these factors in gut epithelial cell development and differentiation.Received 18 October 2002; received after revision 18 December 2002; accepted 18 December 2002     

The function of miRNA in cardiac hypertrophy

Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non-cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed.     

Farnesoid X receptor alpha: a molecular link between bile acids and steroid signaling?

Bile acids are cholesterol metabolites that have been extensively studied in recent decades. In addition to having ancestral roles in digestion and fat solubilization, bile acids have recently been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor farnesoid X receptor (FXRα) or of the G protein-coupled receptor TGR5. In this review, we will focus on the emerging role of FXRα, suggesting important functions for the receptor in steroid metabolism. It has been described that FXRα is expressed in the adrenal glands and testes, where it seems to control steroid production. FXRα also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors. In this review, we discuss the potential impacts of bile acid (BA), through its interactions with steroid metabolism, on glucose metabolism, sexual function, and prostate and breast cancers. Although several of the published reports rely on in vitro studies, they highlight the need to understand the interactions that may affect health. This effect is important because BA levels are increased in several pathophysiological conditions related to liver injuries. Additionally, BA receptors are targeted clinically using therapeutics to treat liver diseases, diabetes, and cancers.     

B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance

Obesity-related insulin resistance is a chronic inflammatory condition that often gives rise to type 2 diabetes (T2D). Much evidence supports a role for pro-inflammatory T cells and macrophages in promoting local inflammation in tissues such as visceral adipose tissue (VAT) leading to insulin resistance. More recently, B cells have emerged as an additional critical player in orchestrating these processes. B cells infiltrate VAT and display functional and phenotypic changes in response to diet-induced obesity. B cells contribute to insulin resistance by presenting antigens to T cells, secreting inflammatory cytokines, and producing pathogenic antibodies. B cell manipulation represents a novel approach to the treatment of obesity-related insulin resistance and potentially to the prevention of T2D. This review summarizes the roles of B cells in governing VAT inflammation and the mechanisms by which these cells contribute to altered glucose homeostasis in insulin resistance.     

Microautophagy: lesser-known self-eating

Microautophagy, the non-selective lysosomal degradative process, involves direct engulfment of cytoplasmic cargo at a boundary membrane by autophagic tubes, which mediate both invagination and vesicle scission into the lumen. With its constitutive characteristics, microautophagy of soluble substrates can be induced by nitrogen starvation or rapamycin via regulatory signaling complex pathways. The maintenance of organellar size, membrane homeostasis, and cell survival under nitrogen restriction are the main functions of microautophagy. In addition, microautophagy is coordinated with and complements macroautophagy, chaperone-mediated autophagy, and other self-eating pathways. Three forms of selective microautophagy, including micropexophagy, piecemeal microautophagy of the nucleus, and micromitophagy, share common ground with microautophagy to some degree. As the accumulation of experimental data, the precise mechanisms that govern microautophagy are becoming more appreciated. Here, we review the microautophagic molecular machinery, its physiological functions, and relevance to human diseases, especially in diseases involving multivesicular bodies and multivesicular lysosomes.     

Sphingosine 1-phosphate increases glucose uptake through trans-activation of insulin receptor

Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts through a family of G-protein-coupled receptors. Herein, we report evidence of a novel redox-based cross-talk between S1P and insulin signaling pathways. In skeletal muscle cells S1P, through engagement of its S1P₂ receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the small GTPase Rac1. S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. This redox-based inhibition of the phosphatase provokes a ligand-independent trans-phosphorylation of insulin receptor and a strong increase in glucose uptake. Our results propose a new role of S1P, recognizing the lipid as an insulin-mimetic cue and pointing at reactive oxygen species as critical regulators of the cross-talk between S1P and insulin pathways. Any possible implication of S1P-directed insulin signaling in diabetes and insulin resistance remains to be established.     

Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy

Bone morphogenetic proteins (BMPs) are important extracellular cytokines that play critical roles in embryogenesis and tissue homeostasis. BMPs signal via transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad effector proteins. BMP signaling is precisely regulated and perturbation of BMP signaling is connected to multiple diseases, including musculoskeletal diseases. In this review, we will summarize the recent progress in elucidation of BMP signal transduction, how overactive BMP signaling is involved in the pathogenesis of heterotopic ossification and Duchenne muscular dystrophy, and discuss possible therapeutic strategies for treatment of these diseases.     

Phosphoinositides and signal transduction

Phosphoinositides comprise a family of eight minor membrane lipids which play important roles in many signal transducing pathways in the cell. Signaling through various phosphoinositides has been shown to mediate cell growth and proliferation, apoptosis, cytoskeletal changes, insulin action and vesicle trafficking. A number of advances in signal transduction in the last decade has resulted in the discovery of a growing list of proteins which directly interact with high affinity and specificity with distinct phosphoinositides. Equally important, a number of phosphoinositide binding domains such as the pleckstrin homology domain have emerged as critical mediators of phosphoinositide signaling. Here, recent advances in phosphoinositide signaling are discussed. The aim of this review is to highlight particularly exciting advances made in the field over the last few years. The regulation of phosphoinositide metabolism by lipid kinases, phosphatases and phospholipases is reviewed, and considerable emphasis is placed on phosphoinositide-binding proteins. Finally, the role of these lipids in regulating signaling pathways and cell function is described.     

Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain

In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling. This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%, or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT) expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion, cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh homeostasis. Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006     

Regulation of insulin receptor function

Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article. Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007     

Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases

Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future.     

Homeostatic and innate immune responses: role of the transmembrane glycoprotein CD98

The transmembrane glycoprotein CD98 is a potential regulator of multiple functions, including integrin signaling and amino acid transport. Abnormal expression or function of CD98 and disruption of the interactions between CD98 and its binding partners result in defects in cell homeostasis and immune responses. Indeed, expression of CD98 has been correlated with diseases such as inflammation and tumor metastasis. Modulation of CD98 expression and/or function therefore represents a promising therapeutic strategy for the treatment and prevention of such pathologies. Herein, we review the role of CD98 with focus on its functional importance in homeostasis and immune responses, which could help to better understand the pathogenesis of CD98-associated diseases.     

Regulatory mechanisms of mitogen-activated kinase signaling

MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction and play essential roles in various physiological processes. There are three main families of MAPKs in mammals, whose functions are regulated by activators, inactivators, substrates and scaffolds, which together form delicate signaling cascades in response to different extracellular or intracellular stimulation. MAPK signaling is tightly regulated so that optimal biological activities are achieved and health is maintained. However, how the specificity of the signaling flow along each cascade is achieved is still relatively unclear. In this review, we summarize recent advances in understanding the regulation of MAPK cascades and the roles of MAP kinases and their regulators in development and in immune responses. Received 11 January 2007; received after revision 31 May 2007; accepted 5 July 2007