细胞信号转导与X连锁的非特异性精神发育迟滞

非特异性精神发育迟滞是患者仅表现出一般或特殊认知功能障碍的一种病症。对相关的基因及其生理功能进行研究,不仅对弄清非特异性精神发育迟滞的遗传基础有重要意义,还能揭示人类认知功能的分子遗传机理。文章对一些涉及X连锁的非特异精神发育迟滞的基因,其表达产物同时参与细胞信号转导的信号分子,如跨膜受体、鸟苷酸相关蛋白和激酶的生理功能及其研究现状进行了阐述,揭示了细胞信号转导与人类认知活动之间的密切关系,为精神发育迟滞的治疗或预防提供新思路。     

综述: MicroRNA与细胞信号通路的相互作用

MicroRNA(miRNA),广泛存在于多种生物中,在基因表达调控的转录后水平上发挥着重要的调节作用．细胞信号通路转导外界刺激进而引发一系列生理和病理效应,决定着细胞的功能和命运．而miRNA和细胞信号通路间的相互作用对于二者的功能发挥起着关键作用,本文将从信号通路对miRNA的调控和miRNA对信号通路的调节两方面综述二者的相互作用,揭示整合miRNA的细胞信号通路及其生物学意义．     

运动与P53调节细胞信号转导通路研究进展

P53调节多个细胞信号转导通路,其功能与肿瘤抑制、细胞周期调控、能量代谢调节、促进线粒体生物发生、保持氧化应激平衡等有关,保持P53基因的稳态表达是预防肿瘤和延缓衰老的策略之一.体育锻炼能促进机体新陈代谢、延缓细胞衰老、减少细胞癌变几率,适宜的运动能够通过影响P53调节的多个细胞信号通路延续P53信号稳态.     

第六届细胞信号转导专题学术讨论会

经细胞生物学会细胞信号转导专业委员会主持召开首次筹备会 (武汉 ,2 0 0 1年 5月 1 9日 )讨论决定 ,原“钙与细胞功能暨细胞信号转导专题学术讨论会”改名为“细胞信号转导专题学术讨论会” ,届时将请多名国内外知名教授作报告。会议欢迎跨学科 (物理、化学等专业 )专家、研究生参加。本会第六届会议将于2 0 0 2年 1 0月在武汉召开 ,主办单位为武汉大学生命科学学院 ,会议名誉主席为该学院杨弘远院士。会议主题内容为 :1 .钙与细胞功能2 .细胞信号转导与细胞生长发育调节3 .细胞信号转导与人类疾病4.细胞信号转导与植物抗逆性论文摘要收取…     

小分子G蛋白R-Ras介导的细胞信号转导通路及其生物学功能

R-Ras属于小分子G蛋白Ras超家族,在细胞信号转导通路中起着分子开关的作用,具有调控细胞黏附、促进细胞凋亡、抑制细胞运动、调节细胞形态等多种生物学功能。R-Ras和Ras家族的其他成员一样,结合GTP时处于激活状态,即信号通路开启状态,能够与下游因子相互作用;通过上游信号的调节及其下游效应物,将胞外信号转导到胞内,调节细胞的相关生物学功能。最近的研究提示R-Ras与乳腺癌等肿瘤的发生具有相关性,对其深入研究有可能为肿瘤发生机制的阐明提供分子基础。我们对R-Ras介导的细胞信号转导通路及其生物学功能进行简要综述。     

生长因子受体酪氨酸激酶的结构与功能

受体酪氨酸蛋白激酶是细胞信号转导进行的关键信号酶,在生长因子调控细胞生长、发育与功能的过程中起着重要的生理作用.本文主要介绍生长因子受体酪氨酸蛋白激酶的分类、结构与功能及其部分相关信号转导机制的研究进展.     

FRET技术在受体信号转导研究中的应用

细胞信号传导是细胞生物学方面的重要内容之一,涉及生命过程的各个方面,包括生长、分化发育、增殖、凋亡、迁移等等,对维持细胞功能及机体生存至关重要。目前对细胞信号转导研究的技术手段多种多样,其中荧光共振能量转移技术（FRET）是研究细胞信号转导较为常用的一种技术,可以实现活细胞内蛋白质之间相互作用的实时检测。本文中我们以受体酪氨酸激酶为例,介绍FRET技术在受体介导细胞信号传导中的应用及进展情况。     

朊粒蛋白正常生理功能研究进展

作为多种神经退行性疾病致病源的朊粒蛋白（PrP^c）是机体内一种正常表达蛋白,其生理功能在神经系统、铜代谢、抗氧化机制、细胞信号转导、细胞凋亡,以及核酸代谢等诸多方面都得到不同形式的表现,本文分类介绍其各种相关功能的研究进展以及研究的思路与方法。     

Notch信号通路的研究现状

Notch信号通路是一条进化上十分保守的信号转导系统。Notch受体通过与配体的相互作用转导细胞信号,从而在细胞增殖、分化、凋亡中发挥重要的调控作用。Notch信号通路平衡细胞增殖、分化、凋亡的重要性提示其可能与肿瘤细胞的异常调控相关。近来研究发现,在许多肿瘤细胞系中存在notch基因的异常活化,且失控的Notch信号与肿瘤细胞的生长调控相关。文章综述了就新近有关Notch信号通路的生理功能及其对肿瘤细胞的调控作用。     

宿主细胞应答病毒感染的细胞信号转导研究新进展

机体如何识别以及清除入侵的病毒一直是分子免疫学研究的重点.早期的研究揭示,病毒的入侵可诱导表达大量的IFNβ,PKR等抗病毒蛋白分子.这些蛋白质分子通过多种方式造成被侵染细胞表现出特殊的状态或迅速凋亡,从而控制病毒的复制和传播,同时诱导产生大量细胞因子和趋化因子等,启动适应性免疫反应的进程.但是,该领域研究的一个重要瓶颈是对于病毒与宿主细胞相互作用的最早期信号事件了解甚微.近几年的研究工作在先天性免疫系统如何识别早期病毒的入侵方面取得了重大进展.TLR3和RIG-I/MDA5细胞信号转导通路,是最近发现的宿主细胞识别与应答病毒的重要调节机制.它们利用不同的细胞信号转导机制诱导先天性免疫反应,主要参与脊椎动物细胞识别和清除RNA病毒的原发抗感染过程,是机体先天免疫系统的一种重要反应机制,直接影响后续适应性免疫系统的作用.就这些细胞信号转导通路在先天性免疫应答中的研究进展做了概述与展望.     

Slit-Robo signaling mediates lymphangiogenesis and promotes tumor lymphatic metastasis

The Slit family of guidance cues binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit-Robo signaling had been reported to function as chemoattractive signal for vascular endothelial cells during angiogenesis. In this study, we found that Robo1 was expressed in lymphatic endothelial cells to mediate the migration and tube formation of these cells upon Slit2 stimulation, which were specifically inhibited by the function-blocking antibody R5 to Slit2/Robo1 interaction. To further explore the lymphangiogenic effect and significance mediated by Slit-Robo signaling, we intercrossed Slit2 transgenic mice with a non-metastatic RIP1-Tag2 mouse tumor model, and found that transgenic overexpression of Slit2 significantly enhanced tumor lymphangiogenesis and subsequently promoted mesenteric lymph node metastasis of pancreatic islet tumors. Taken together, our findings reveal that through interacting with Robo1, Slit2 is a novel and potent lymphangiogenic factor and contributes to tumor lymphatic metastasis.     

Role of Slit/Robo Signaling pathway in Bone Metabolism

Slit/Robo signals were initially found to play an essential role in nerve development as axonal guidance molecules. In recent years, with in-depth study, the role of Slit/Robo in other life activities, such as tumor development, angiogenesis, cell migration, and bone homeostasis, has gradually been revealed. Bone is an organ with an active metabolism. Bone resorption and bone formation are closely related through precise spatiotemporal coordination. There is much evidence that slit, as a new bone coupling factor, can regulate bone formation and resorption. For example, Slit3 can promote bone formation and inhibit bone resorption through Robo receptors, which has excellent therapeutic potential in metabolic bone diseases. Although the conclusions of some studies are contradictory, they all affirm the vital role of Slit/Robo signaling in regulating bone metabolism. This paper reviews the research progress of Slit/Robo signaling in bone metabolism, briefly discusses the contradictions in the existing research, and puts forward the research direction of Slit/Robo in the field of bone metabolism in the future.     

Structural and functional analysis of slit and heparin binding to immunoglobulin-like domains 1 and 2 of Drosophila Robo

Recognition of the secreted protein Slit by transmembrane receptors of the Robo family provides important signals in the development of the nervous system and other organs, as well as in tumor metastasis and angiogenesis. Heparan sulfate (HS) proteoglycans serve as essential co-receptors in Slit-Robo signaling. Previous studies have shown that the second leucinerich repeat domain of Slit, D2, binds to the N-terminal immunoglobulin-like domains of Robo, IG1-2. Here we present two crystal structures of Drosophila Robo IG1-2, one of which contains a bound heparin-derived oligosaccharide. Using structure-based mutagenesis of a Robo IG1-5 construct we identified key Slit binding residues (Thr-74, Phe-114, Arg-117) forming a conserved patch on the surface of IG1; mutation of similarly conserved residues in IG2 had no effect on Slit binding. Mutation of conserved basic residues in IG1 (Lys-69, Arg-117, Lys-122, Lys-123), but not in IG2, reduced binding of Robo IG1-5 to heparin, in full agreement with the Robo-heparin co-crystal structure. Our collective results, together with a recent crystal structure of a minimal human Slit-Robo complex ( Morlot, C., Thielens, N. M., Ravelli, R. B., Hemrika, W., Romijn, R. A., Gros, P., Cusack, S., and McCarthy, A. A. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 14923-14928 ), reveal a contiguous HS/heparin binding surface extending across the Slit-Robo interface. Based on the size of this composite binding site, we predict that at least five HS disaccharide units are required to support Slit-Robo signaling.     

A molecular mechanism for the heparan sulfate dependence of slit-robo signaling

Slit is a large secreted protein that provides important guidance cues in the developing nervous system and in other organs. Signaling by Slit requires two receptors, Robo transmembrane proteins and heparan sulfate (HS) proteoglycans. How HS controls Slit-Robo signaling is unclear. Here we show that the second leucine-rich repeat domain (D2) of Slit, which mediates binding to Robo receptors, also contains a functionally important binding site for heparin, a highly sulfated variant of HS. Heparin markedly enhances the affinity of the Slit-Robo interaction in a solid-phase binding assay. Analytical gel filtration chromatography demonstrates that Slit D2 associates with a soluble Robo fragment and a heparin-derived oligosaccharide to form a ternary complex. Retinal growth cone collapse triggered by Slit D2 requires cell surface HS or exogenously added heparin. Mutation of conserved basic residues in the C-terminal cap region of Slit D2 reduces heparin binding and abolishes biological activity. We conclude that heparin/HS is an integral component of the minimal Slit-Robo signaling complex and serves to stabilize the relatively weak Slit-Robo interaction.     

The role of Slit-Robo signaling in the generation, migration and morphological differentiation of cortical interneurons

Cortical interneurons in rodents are generated in the ventral telencephalon and migrate tangentially into the cortex. This process requires the coordinated action of many intrinsic and extrinsic factors. Here we show that Robo1 and Robo2 receptor proteins are dynamically expressed throughout the period of corticogenesis and colocalize with interneuronal markers, suggesting that they play a role in the migration of these cells. Analysis of Robo mutants showed a marked increase in the number of interneurons in the cortices of Robo1^−/−, but not Robo2^−/−, animals throughout the period of corticogenesis and in adulthood; this excess number of interneurons was observed in all layers of the developing cortex. Using BrdU incorporation in dissociated cell cultures and phosphohistone-3 labeling in vivo, we demonstrated that the increased number of interneurons in Robo1^−/− mice is, at least in part, due to increased proliferation. Interestingly, a similar increase in proliferation was observed in Slit1^−/−/Slit2^−/− mutant mice, suggesting that cell division is influenced by Slit-Robo signaling mechanisms. Morphometric analysis of migrating interneurons in Robo1^−/−, Robo2^−/− and Slit1^−/−/Slit2^−/−, but not in Slit1^−/− mice, showed a differential increase in neuronal process length and branching suggesting that Slit-Robo signaling also plays an important role in the morphological differentiation of these neurons.     

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis.     

Human placental multipotent mesenchymal stromal cells modulate placenta angiogenesis through Slit2-Robo signaling

abstract

The objective of this study was to investigate whether human placental multipotent mesenchymal stromal cell (hPMSC)-derived Slit2 and endothelial cell Roundabout (Robo) receptors are involved in placental angiogenesis. The hPMSC-conditioned medium and human umbilical vein endothelial cells were studied for Slit2 and Robo receptor expression by immunoassay and RT-PCR. The effect of the conditioned medium of hPMSCs with or without Slit2 depletion on endothelial cells was investigated by in vitro angiogenesis using growth factor-reduced Matrigel. hPMSCs express Slit2 and both Robo1 and Robo4 are present in human umbilical vein endothelial cells. Human umbilical vein endothelial cells do not express Robo2 and Robo3. The hPMSC-conditioned medium and Slit2 recombinant protein significantly inhibit the endothelial cell migration, but not by the hPMSC-conditioned medium with Slit2 depletion. The hPMSC-conditioned medium and Slit2 significantly enhance endothelial tube formation with increased cumulated tube length, polygonal network number and vessel branching point number compared to endothelial cells alone. The tube formation is inhibited by the depletion of Slit2 from the conditioned medium, or following the expression of Robo1, Robo4, and both receptor knockdown using small interfering RNA. Furthermore, co-immunoprecipitation reveals Slit2 binds to Robo1 and Robo4. Robo1 interacts and forms a heterodimeric complex with Robo4. These results suggest the implication of both Robo receptors with Slit2 signaling, which is involved in endothelial cell angiogenesis. Slit2 in the conditioned medium of hPMSCs has functional effect on endothelial cells and may play a role in placental angiogenesis.     

Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis

Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.     

Roundabout 2 regulates migration of sensory neurons by signaling in trans

BACKGROUND: Roundabout (Robo) receptors and their ligand Slit are important regulators of axon guidance and cell migration. The development of Drosophila embryonic sense organs provides a neuronal migration paradigm where the in vivo roles of Slit and Robo can be assayed using genetics. RESULTS: Here we show that Slit-Robo signaling controls migration of Drosophila larval sensory neurons that are part of the Chordotonal (Cho) stretch receptor organs. We used live imaging to show that abdominal Cho organs normally migrate ventrally during development, whereas thoracic Cho organs do not. Robo2 overexpression in cis (in the sensory neurons) or in trans (on neighboring visceral mesoderm) transforms abdominal organs to a thoracic morphology and position by blocking migration, while loss of Slit-Robo signaling produces a reverse transformation in which thoracic organs migrate ectopically. Rescue and tissue-specific knockout experiments indicate that trans signaling by Robo2 contributes to the normal positioning of the thoracic Cho organs. The differential positioning of Cho organs between the thorax and abdomen is known to be regulated by Hox genes, and we show that the essential Hox cofactor Homothorax, represses Robo2 expression in the abdominal visceral mesoderm. CONCLUSIONS: Our results suggest that segment-specific neuronal migration patterns are directed through a novel signaling complex (the "Slit sandwich") in which Robo2 on the thoracic visceral mesoderm binds to Slit and presents it to Robo receptors on Cho neurons. The differential positioning of Cho organs between thorax and abdomen may be determined by Hox gene-mediated repression of robo2.     

GAPs in Slit-Robo signaling

Neuronal migration requires the integration of a number of diverse environmental cues and subsequent translation to specific responses such as directed cytoskeletal remodeling. Accurate knowledge of the signal transduction pathways linking activation of surface receptors to actin dynamics is necessary in order to understand the regulation of such processes. Activation of the Roundabout (Robo) receptor mediates a repulsive response in certain pioneering axons and migratory neurons. Recently, Wong et al have described a signaling link between Robo activation and specific GTPase activity that appears to regulate neuronal migration. A novel family of GTPase regulators, responsive to Slit-Robo engagement, has been identified and convincingly shown to alter the migration of neuronal cells. This study not only delineates a specific signaling route from guidance receptors to directed neuronal movement, but also offers clues towards potential regulatory mechanisms that ensure specificity of the Slit-Robo response.