Multiplicity of the interactions of Wnt proteins and their receptors

Wnts are secreted proteins that are essential for a wide array of developmental and physiological processes. They signal across the plasma membranes by interacting with serpentine receptors of the Frizzled (Fz) family and members of the low-density-lipoprotein receptor-related protein (LRP) family. Recent advances in the Wnt signaling field have revealed that Wnt-unrelated proteins activate or suppress Wnt signaling by binding to Fzs or LRP5/6 and that atypical receptor tyrosine kinases mediate Wnt signaling independently of Fz and/or function as a Fz co-receptor. This review highlights recent progress in our understanding of the multiplicity of Wnts and their receptors. We discuss how the interaction between the ligands and receptors activate distinct intracellular signaling pathways. We also discuss how intracellular trafficking of Wnt signaling components can regulate the sensitivity of cells to Wnts.     

Regulation of the LPA2 receptor signaling through the carboxyl-terminal tail-mediated protein-protein interactions

While it is well known that lysophosphatidic acid (LPA) mediates diverse physiological and pathophysiological responses through the activation of G protein-coupled LPA receptors, the specificity and molecular mechanisms by which different LPA receptors mediate these biological responses remain largely unknown. Recent identification of several PDZ proteins and zinc finger proteins that interact with the carboxyl-terminal tail of the LPA(2) receptor provides a considerable progress towards the understanding of the mechanisms how the LPA(2) receptor specifically mediates LPA signaling pathways. These findings have led to the proposal that there are at least two distinct protein interaction motifs present in the carboxyl-terminus of the LPA(2) receptor. Together, these data provide a new concept that the efficiency and specificity of the LPA(2) receptor-mediated signal transduction can be achieved through the cross-regulation between the classical G protein-activated signaling cascades and the interacting partner-mediated signaling pathways.     

TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding

The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCζ upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions.     

Alternative Splicing of the RAGE Cytoplasmic Domain Regulates Cell Signaling and Function

The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor present on most cell types. Upregulation of RAGE is seen in a number of pathological states including, inflammatory and vascular disease, dementia, diabetes and various cancers. We previously demonstrated that alternative splicing of the RAGE gene is an important mechanism which regulates RAGE signaling through the production of soluble ligand decoy isoforms. However, no studies have identified any alternative splice variants within the intracellular region of RAGE, a region critical for RAGE signaling. Herein, we have cloned and characterized a novel splice variant of RAGE that has a truncated intracellular domain (RAGEΔICD). RAGEΔICD is prevalent in both human and mouse tissues including lung, brain, heart and kidney. Expression of RAGEΔICD in C6 glioma cells impaired RAGE-ligand induced signaling through various MAP kinase pathways including ERK1/2, p38 and SAPK/JNK. Moreover, RAGEΔICD significantly affected tumor cell properties through altering cell migration, invasion, adhesion and viability in C6 glioma cells. Furthermore, C6 glioma cells expressing RAGEΔICD exhibited drastic inhibition on tumorigenesis in soft agar assays. Taken together, these data indicate that RAGEΔICD represents a novel endogenous mechanism to regulate RAGE signaling. Significantly, RAGEΔICD could play an important role in RAGE related disease states through down regulation of RAGE signaling.     

5-HT1A receptor-regulated signal transduction pathways in brain

Serotonin is an influential monoamine neurotransmitter that signals through a number of receptors to modulate brain function. Among different serotonin receptors, the serotonin 1A (5-HT1A) receptors have been tied to a variety of physiological and pathological processes, notably in anxiety, mood, and cognition. 5-HT1A receptors couple not only to the classical inhibitory G protein-regulated signaling pathway, but also to signaling pathways traditionally regulated by growth factors. Despite the importance of 5-HT1A receptors in brain function, little is known about how these signaling mechanisms link 5-HT1A receptors to regulation of brain physiology and behavior. Following a brief summary of the known physiological and behavioral effects of 5-HT1A receptors, this article will review the signaling pathways regulated by 5-HT1A receptors, and discuss the potential implication of these signaling pathways in 5-HT1A receptor-regulated physiological processes and behaviors.     

Signaling Circuits on the Golgi Complex

Numerous components of signaling pathways involved in key cellular processes reside on the Golgi complex. Here, we will focus on the roles of signaling proteins that regulate cargo trafficking along the anterograde and retrograde pathways. Emphasis will also be put on the effects of these regulatory proteins on the maintenance of the structure and function of the Golgi, and in particular on the phosphorylation of key components of the transport machinery. These pathways position the Golgi complex as a central hub in the regulation of cell signaling. To date, however, the activation and coordination of these signaling molecules remain a mystery. Being able to describe the interplay between several of these signaling pathways and secretion, and the flow of information through these pathways, will help us to understand how the secretory machinery works and how it interacts with other cellular functions. This will also advance our understanding of how the secretory pathway functions under physiological circumstances, and how its dysregulation can initiate pathological conditions.     

上皮细胞转分化的信号转导研究进展及其在肾小管的研究现状

上皮细胞在特定生理和病理情况下向间充质细胞转分化的现象是肿瘤及慢性炎症性疾病中的重要细胞生物学现象。近年来研究发现 ,细胞内信号转导途径中的MAPK通路、Rho家族激酶、Src激酶、PI3激酶和Smad通路参与调控上皮细胞转分化过程。肾小管上皮细胞在病理条件下可转分化为肌成纤维细胞 ,其细胞内信号转导机制虽已有初步研究 ,但尚所知甚少。本文将就有关的研究进展及现状进行综述     

Mechanisms and functions of AT(1) angiotensin receptor internalization

The type 1 (AT(1)) angiotensin receptor, which mediates the known physiological and pharmacological actions of angiotensin II, activates numerous intracellular signaling pathways and undergoes rapid internalization upon agonist binding. Morphological and biochemical studies have shown that agonist-induced endocytosis of the AT(1) receptor occurs via clathrin-coated pits, and is dependent on two regions in the cytoplasmic tail of the receptor. However, it is independent of G protein activation and signaling, and does not require the conserved NPXXY motif in the seventh transmembrane helix. The dependence of internalization of the AT(1) receptor on a cytoplasmic serine-threonine-rich region that is phosphorylated during agonist stimulation suggests that endocytosis is regulated by phosphorylation of the AT(1) receptor tail. beta-Arrestins have been implicated in the desensitization and endocytosis of several G protein-coupled receptors, but the exact nature of the adaptor protein required for association of the AT(1) receptor with clathrin-coated pits, and the role of dynamin in the internalization process, are still controversial. There is increasing evidence for a role of internalization in sustained signal generation from the AT(1) receptor. Several aspects of the mechanisms and specific function of AT(1) receptor internalization, including its precise mode and route of endocytosis, and the potential roles of cytoplasmic and nuclear receptors, remain to be elucidated.     

Coupled Stochastic Spatial and Non-Spatial Simulations of ErbB1 Signaling Pathways Demonstrate the Importance of Spatial Organization in Signal Transduction

Background

The ErbB family of receptors activates intracellular signaling pathways that control cellular proliferation, growth, differentiation and apoptosis. Given these central roles, it is not surprising that overexpression of the ErbB receptors is often associated with carcinogenesis. Therefore, extensive laboratory studies have been devoted to understanding the signaling events associated with ErbB activation.

Methodology/Principal Findings

Systems biology has contributed significantly to our current understanding of ErbB signaling networks. However, although computational models have grown in complexity over the years, little work has been done to consider the spatial-temporal dynamics of receptor interactions and to evaluate how spatial organization of membrane receptors influences signaling transduction. Herein, we explore the impact of spatial organization of the epidermal growth factor receptor (ErbB1/EGFR) on the initiation of downstream signaling. We describe the development of an algorithm that couples a spatial stochastic model of membrane receptors with a nonspatial stochastic model of the reactions and interactions in the cytosol. This novel algorithm provides a computationally efficient method to evaluate the effects of spatial heterogeneity on the coupling of receptors to cytosolic signaling partners.

Conclusions/Significance

Mathematical models of signal transduction rarely consider the contributions of spatial organization due to high computational costs. A hybrid stochastic approach simplifies analyses of the spatio-temporal aspects of cell signaling and, as an example, demonstrates that receptor clustering contributes significantly to the efficiency of signal propagation from ligand-engaged growth factor receptors.     

A novel improved therapy strategy for diabetic nephropathy

Diabetic nephropathy (DN), is a disorder that causes significant morbidity and mortality. Studies on the pathological mechanisms of DN reveal that advanced glycation end products (AGEs) play an important role in the pathogenesis of DN through interacting with receptors for advanced glycation end products (RAGE), which activate a series of intracellular signaling pathways. AGEs and RAGE have therefore been considered to be two potential key targets. Although multiple studies have been made for anti-DN therapy against AGEs or RAGE, the results have been disappointing due to poor effectiveness or to side effects in clinical practice. In this hypothesis article, we propose a novel treatment based on a dual-target approach. A kind of multi-functional intelligent nanoparticle is constructed, which has a core-shell nanoparticle structure to load the dual-target drugs (AGEs inhibitors and RAGE inhibitors), and has a functional “RAGE analog” to be used as “bait” to catch AGEs and target them to the kidney. Owing to its advantages of having a dual-target, synergistic effect and high efficiency, the proposition may have potential applications in DN therapy.     

A novel improved therapy strategy for diabetic nephropathy: Targeting AGEs

Diabetic nephropathy (DN), is a disorder that causes significant morbidity and mortality. Studies on the pathological mechanisms of DN reveal that advanced glycation end products (AGEs) play an important role in the pathogenesis of DN through interacting with receptors for advanced glycation end products (RAGE), which activate a series of intracellular signaling pathways. AGEs and RAGE have therefore been considered to be two potential key targets. Although multiple studies have been made for anti-DN therapy against AGEs or RAGE, the results have been disappointing due to poor effectiveness or to side effects in clinical practice. In this hypothesis article, we propose a novel treatment based on a dual-target approach. A kind of multi-functional intelligent nanoparticle is constructed, which has a core-shell nanoparticle structure to load the dual-target drugs (AGEs inhibitors and RAGE inhibitors), and has a functional "RAGE analog" to be used as "bait" to catch AGEs and target them to the kidney. Owing to its advantages of having a dual-target, synergistic effect and high efficiency, the proposition may have potential applications in DN therapy.     

Opioid Receptor Trafficking and Signaling: What Happens After Opioid Receptor Activation?

Prolonged opioid treatment leads to a comprehensive cellular adaptation mediated by opioid receptors, a basis to understand the development of opioid tolerance and dependence. However, the molecular mechanisms underlying opioid-induced cellular adaptation remain obscure. Recent advances in opioid receptor trafficking and signaling in cells have extensively increased our insight into the network of intracellular signal integration. This review focuses on those important intracellular biochemical processes that play critical roles in the development of opioid tolerance and dependence after opioid receptor activation, and tries to explain what happens after opioid receptor activation, and how the cellular adaptation develops from cell membrane to nucleus. Decades of research have delineated a network on opioid receptor trafficking and signaling, but the challenge remains to explain opioid tolerance and dependence from a single cellular signal network.     

Inhibitory receptors on lymphocytes: insights from infections

Costimulatory and inhibitory receptors are critical regulators of adaptive immune cell function. These pathways regulate the initiation and termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. This review focuses on recent advances in our understanding of inhibitory receptor pathways and their roles in different diseases and/or infections, emphasizing potential clinical applications and important unanswered mechanistic questions. Although significant progress has been made in defining the influence of inhibitory receptors at the cellular level, relatively little is known about the underlying molecular pathways. We discuss our current understanding of the molecular mechanisms for key inhibitory receptor pathways, highlight major gaps in knowledge, and explore current and future clinical applications.     

Short Forms of Membrane Receptors: Generation and Role in Hormonal Signal Transduction

This review highlights the generation of various types of short forms of membrane hormonal receptors and the mode of regulation of their tissue-specific patterns. The short forms of membrane receptors are classified on the basis of localization of missing functional fragments. The review provides examples of tissues for which expression of short forms may serve as a marker of changes of ontogenetic stage, physiological state, or the development of pathological process. The short forms of receptors are shown to participate in determining tissue-specificity and efficacy of hormonal signal transduction, as well as in transport of hormones within cell, through physiological barriers, and in blood circulation. Peculiarities of signal transduction pathways for short receptor forms and potential physiological significance of these forms are analyzed. It is concluded that the ratio of long and short receptor forms may serve as a key marker of dynamic changes of differentiation stage and alterations of metabolic and proliferative activity of tissues under normal and pathologic conditions, and thus to be an important indicator of therapeutic effect for many pathological processes.     

G protein-coupled receptor-induced Akt activity in cellular proliferation and apoptosis

Akt (also known as protein kinase B) plays an integral role in many intracellular signaling pathways activated by a diverse array of extracellular signals that target several different classes of membrane-bound receptors. Akt plays a particularly prominent part in signaling networks that result in the modulation of cellular proliferation, apoptosis and survival. Thus, the overexpression of Akt subtypes has been measured in a number of cancer types, and dominant-negative forms of Akt can trigger apoptosis and reduce the survival of cancer cells. G protein-coupled receptors act as cell-surface detectors for a diverse spectrum of biological signals and are able to activate or inhibit Akt via several direct and indirect means. In this review, we shall document how G protein-coupled receptors are able to control Akt activity and examine the resulting biochemical and physiological changes, with particular emphasis on cellular proliferation, apoptosis and survival.     

Opposing roles of RAGE and Myd88 signaling in extensive liver resection

In extensive liver resection secondary to primary or metastatic liver tumors, or in living donor liver transplantation, strategies to quell deleterious inflammatory responses and facilitate regeneration are essential. The receptor for advanced glycation endproducts (RAGE) and myeloid differentiating factor 88 (Myd88) are implicated in the inflammatory response. To establish the contributions of RAGE vs. Myd88 signaling in extensive liver resection, we probed the effect of RAGE and/or Myd88, the latter primarily a key transducer of major toll-like receptors and also implicated in interleukin-1 (Il1) signaling, in a murine model of extensive (85%) hepatectomy. We report that, although Myd88 is thoroughly essential for survival via regulation of NF-κB and TNF-α, deletion of RAGE significantly improved survival compared to wild-type, Myd88-null, or RAGE-null/Myd88-null mice. RAGE opposes Myd88 signaling at multiple levels: by suppression of p65 levels, thereby reducing activation of NF-κB and consequent production of cyclin D1, and by suppression of Il6-mediated phosphorylation of Stat3, thereby down-regulating Pim1 and suppressing the hyperplastic response. Further, RAGE-dependent suppression of glyoxalase1, a detoxification pathway for pre-AGEs, enhances AGE levels and suppresses Il6 action. We conclude that blockade of RAGE may rescue liver remnants from the multiple signals that preclude adaptive proliferation triggered primarily by Myd88 signaling pathways.