Oxysterols are allosteric activators of the oncoprotein Smoothened

Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms.     

中枢白细胞介素-1系统及信号转导研究进展

中枢白细胞介素 1(centralinterleukin 1,IL 1)以及功能和结构相关的分子已构成相对独立的中枢IL 1系统 (IL 1system)。IL 1系统的研究不断深入 ,新成员及其功能不断被发现 ,极大地扩展了该系统新老成员的生物学作用、信号转导通路 ,以及相互之间的联系。本文总结了近几年关于中枢IL 1系统的研究进展 ,包括IL 1系统新成员、信号转导通路和新的信号分子 ,以及IL 1系统与某些生理过程或病理生理过程的关系。     

MiRNA在TLR信号通路中的负性调控作用

TLR信号是生物体重要的病原体模式识别信号,在免疫识别和炎症反应中具有重要作用,其信号异常会导致许多免疫和炎症相关疾病的发生,因此探讨和明确TLR信号通路的调控机制具有非常重要的意义。近年来研究发现,作为重要的基因表达调控的小分子RNA,微RNA(microRNA,miRNA)能与TLR信号通路中众多靶基因mRNA的3’UTR区结合,从而抑制翻译过程或降解mRNA来发挥负性调控作用。本文就miRNA对TLR信号通路中的一些受体、信号分子、调节因子和细胞因子的负性调控作用方面进行阐述。     

Principles of the activin receptor signaling pathway and its inhibition

This review captures the anabolic and stimulatory effects observed with inhibition of the transforming growth factor β superfamily in muscle, blood, and bone. New medicinal substances that rectify activin, myostatin, and growth differentiation factor 11 signaling give hope to the many whose lives are affected by deterioration of these tissues. The review first covers the origin, structure, and common pathway of activins, myostatin, and growth differentiation factor 11 along with the pharmacodynamics of the new class of molecules designed to oppose the activin receptor signaling pathway. Current terminology surrounding this new class of molecules is inconsistent and does not infer functionality. Adopting inhibitors of the activin receptor signaling pathway (IASPs) as a generic term is proposed because it encapsulates the molecular mechanisms along the pathway trajectory. To conclude, a pragmatic classification of IASPs is presented that integrates functionality and side effects based on the data available from animals and humans. This provides researchers and clinicians with a tool to tailor IASPs therapy according to the need of projects or patients and with respect to side effects.     

Insulin signaling pathways in time and space

Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism.     

选择性标记法及脂类信号转导途径的检测

确定由脂类分子介导的信号转导途径和细胞内某些信使分子的生成及改变是信号转导研究领域中的一个重要组成部分.如确定不同磷脂酶活性的调控及细胞内不同来源的第二信使分子及其他脂类生物活性分子的生成与调节,成为探讨生长因子或其他许多分子的生物效应及其作用机理的重要研究内容.为了增加人们对有关研究工作的了解及在方法上的选择,介绍了研究脂类代谢信号转导中广泛运用的一个基本而重要的方法——选择性标记法,并且以实际研究结果为例,说明如何运用该方法检测不同的信号传递途径和有关信号分子的生成与变化.该法针对性强而灵活,重复性高,能有效地检测某些不同来源的信号传递分子的生成及其变化.此外,对脂类代谢信号转导途径及对该途径的研究在信号转导领域的地位和意义也作了简要的介绍.     

The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer

Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFalpha and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies.     

Comparative analysis of the signaling capabilities of the insulin receptor-related receptor

Although insulin receptor (InsR) and type I insulin-like growth factor receptor (IGF-IR) elicit different physiological effects in their target tissues, their signaling capabilities are similar to a large extent. In the present work, we investigated the potential of the third member of the family, insulin receptor-related receptor (IRR), to associate with known interaction partners of the InsR and the IGF-I receptor in a yeast two-hybrid assay. Using the intracellular part of the IRR we found no association with any of the tested signaling molecules. Phosphotyrosine detection revealed a lack in the constitutive activation of the IRR described for analogous constructs of the two other members of the family. Replacement of the kinase domain of the IGF-IR or its C-terminal lobe alone into the IRR caused a complete restoration of the tyrosine phosphorylation of the IRR. The reestablishment of autophosphorylation was paralleled by restoration of interaction with a specific range of signaling molecules.     

Regulation of physiological aspects in plants by hydrogen sulfide and nitric oxide under challenging environment

Plants are exposed to a plethora of abiotic stresses such as drought, salinity, heavy metal and temperature stresses at different stages of their life cycle, from germination to seedling till the reproductive phase. As protective mechanisms, plants release signaling molecules that initiate a cascade of stress-signaling events, leading either to programmed cell death or plant acclimation. Hydrogen sulfide (H₂S) and nitric oxide (NO) are considered as new ‘gasotransmitter’ molecules that play key roles in regulating gene expression, posttranslational modification (PTM), as well as cross-talk with other hormones. Although the exact role of NO in plants remains unclear and is species dependent, various studies have suggested a positive correlation between NO accumulation and environmental stress in plants. These molecules are also involved in a large array of stress responses and act synergistically or antagonistically as signaling components, depending on their respective concentration. This study provides a comprehensive update on the signaling interplay between H₂S and NO in the regulation of various physiological processes under multiple abiotic stresses, modes of action and effects of exogenous application of these two molecules under drought, salt, heat and heavy metal stresses. However, the complete picture of the signaling cascades mediated by H₂S and NO is still elusive. Recent researches indicate that during certain plant processes, such as stomatal closure, H₂S could act upstream of NO signaling or downstream of NO in response to abiotic stresses by improving antioxidant activity in most plant species. In addition, PTMs of antioxidative pathways by these two molecules are also discussed.     

Microtubules and signal transduction

Although molecular components of signal transduction pathways are rapidly being identified, how elements of these pathways are positioned spatially and how signals traverse the intracellular environment from the cell surface to the nucleus or to other cytoplasmic targets are not well understood. The discovery of signaling molecules that interact with microtubules (MTs), as well as the multiple effects on signaling pathways of drugs that destabilize or hyperstabilize MTs, indicate that MTs are likely to be critical to the spatial organization of signal transduction. MTs themselves are also affected by signaling pathways and this may contribute to the transmission of signals to downstream targets.     

Disruption of gap junctional communication by the platelet-derived growth factor is mediated via multiple signaling pathways

The platelet-derived growth factor (PDGF) mediates its cellular functions via activation of its receptor tyrosine kinase followed by the recruitment and activation of several signaling molecules. These signaling molecules then initiate specific signaling cascades, finally resulting in distinct physiological effects. To delineate the PDGF signaling pathway responsible for the disruption of gap junctional communication (GJC), wild-type PDGF receptor beta (PDGFRbeta) and a series of PDGFRbeta mutants were expressed in T51B rat liver epithelial cells. In cells expressing wild-type PDGFRbeta, PDGF induced disruption of GJC and phosphorylation of a gap junctional protein, connexin-43 (Cx43), which required activation of mitogen-activated protein kinase, although involvement of additional factors was also evident. In the F5 mutant lacking binding sites for phosphatidylinositol 3-kinase, GTPase-activating protein, SHP-2, and phospholipase Cgamma1 (PLCgamma1), PDGF induced mitogen-activated protein kinase, but failed to affect GJC or Cx43, indicating involvement of additional signals presumably initiated by one or more of the mutated binding sites. Examination of the single-site mutants revealed that PDGF effects were not mediated via a single signaling component. This was confirmed by the "add-back" mutants, which showed that restoration of either SHP-2 or PLCgamma1 binding was sufficient to propagate the GJC inhibitory actions of PDGF. Further analysis showed that activation of PLCgamma1 is involved in Cx43 phosphorylation, which surprisingly failed to correlate with GJC blockade. The results of our study demonstrate that PDGF-induced disruption of GJC can be mediated by multiple signaling pathways and requires participation of multiple components.     

EGFR配体生物学效应的多样性

表皮生长因子受体（epidermal growth factor receptor, EGFR）的配体作为一类重要的信号分子参与了细胞功能的调节,并且和机体发育、器官形成、组织修复与稳态维持,以及疾病的发生密切相关。虽然这些信号分子具有序列和结构上的相似性,但由于这些信号分子结构上的细微差异以及它们受体信号传导上的复杂性,造成了这些信号分子（配体）生物学效应的多样性。目前,从结构和机制上,对于单个信号分子的生物学效应已有较为深入的研究,但这些信号分子之间以及信号分子与受体之间的调控网络较为复杂,并且这种调控网络对信号的精细、有序和多样化转导至关重要。本文对EGFR配体的结构及配体生物学效应多样性的分子机制进行回顾,并对未来的研究方向提出展望。     

EGFR配体生物学效应的多样性

表皮生长因子受体（epidermal growth factor receptor, EGFR）的配体作为一类重要的信号分子参与了细胞功能的调节,并且和机体发育、器官形成、组织修复与稳态维持,以及疾病的发生密切相关。虽然这些信号分子具有序列和结构上的相似性,但由于这些信号分子结构上的细微差异以及它们受体信号传导上的复杂性,造成了这些信号分子（配体）生物学效应的多样性。目前,从结构和机制上,对于单个信号分子的生物学效应已有较为深入的研究,但这些信号分子之间以及信号分子与受体之间的调控网络较为复杂,并且这种调控网络对信号的精细、有序和多样化转导至关重要。本文对EGFR配体的结构及配体生物学效应多样性的分子机制进行回顾,并对未来的研究方向提出展望。     

Membrane-Associated Non-Receptors and Morphogen Gradients

A previously investigated basic model (System B) for the study of signaling morphogen gradient formation that allows for reversible binding of morphogens (aka ligands) with signaling receptors, degradation of bound morphogens and diffusion of unbound morphogens is extended to include the effects of membrane-bound non-signaling molecules (or non-receptors for short) such as proteoglycans that bind reversibly with the same morphogens and degrade them. Our main goal is to delineate the effects of the presence of non-receptors on the existence and properties of the steady-state concentration gradient of signaling ligand–receptor complexes. Stability of the steady-state morphogen gradients is established and the time to reach steady-state behavior after the onset of morphogen production will be analyzed. The theoretical findings offer explanations for observations reported in several previous experiments on Drosophila wing imaginal discs.     

Ceramide and cell death receptor clustering

Acid sphingomyelinase (ASM) has been shown to be activated by a variety of receptor molecules and stimuli including CD95, the tumor necrosis factor receptor (TNF-R), CD40, CD28, LFA-1, CD5, during development, irradiation, heat shock, UV light or bacterial and viral infections. The central role of ASM-released ceramide in the response to those stimuli is confirmed by several genetic studies. ASM and ceramide might mediate their biological effects by the activation of several intracellular signaling molecules including cathepsin D, phospholipase A(2) or the kinase suppressor of Ras. In addition, recent fluorescence microscopy studies indicate that distinct, small membrane domains, termed rafts, are modified by ceramide to form larger domains, which serve to cluster receptor molecules. The generation of a high receptor density might be required for initiation of receptor-specific signaling and explain the function of the ASM and ceramide in multiple signaling pathways.     

HIV Nef inhibits T cell migration

Nef is a viral regulatory protein of the human immunodeficiency virus (HIV) that has been shown to contribute to disease progression. Among its putative effects on T cell functions are the down-regulation of CD4 and major histocompatibility class I surface molecules. These effects occur in part via Nef interactions with intracellular signaling molecules. We sought to better characterize the effects of HIV Nef on T cell function by examining chemotaxis in response to stromal cell-derived factor-1alpha (SDF-1alpha) as well as CXCR4 signaling molecules. Here, we report the novel observation that HIV Nef inhibited chemotaxis in response to SDF-1alpha in both Jurkat T cells and primary peripheral CD4+ T lymphocytes. Our data indicate that HIV Nef altered critical downstream molecules in the CXCR4 pathway, including focal adhesion kinases. These findings suggest that HIV Nef may blunt the T cell response to chemokines. Because T lymphocyte migration is an integral component of host defense, HIV Nef may thereby contribute to the pathogenesis of AIDS.