Eph/ephrin信号通路对损伤后中枢神经功能的影响研究进展

Eph受体家族是已知最大的酪氨酸激酶受体家族。Eph受体与其配体ephrin具有高度的亲和力,相互作用后可诱发双向的信号传导作用,调节不同的生理活动。由疾病引起的神经损伤如脑卒中,通常会造成突触效能降低、神经元死亡最终导致神经功能缺失,多数神经损伤疾病目前还没有真正有效的治疗手段。研究发现,Eph/ephrin无论在发育个体还是在成年个体的神经系统中都有重要的作用,如细胞的增殖分化及引导、神经网络的构建等。神经损伤后,Eph/ephrin的各种亚型在神经系统中有不同程度的表达上调。在损伤后神经功能下降的情况下,Eph/ephrin可通过激活NM-DA和非NMDA等与突触可塑性相关的途径、调节树突棘、调节突触可塑性相关蛋白等途径来恢复神经功能;还可通过激活趋化因子等促进内源性神经干细胞的增殖、分化和迁徙。Eph/ephrin信号通路为我们提供了一个治疗神经损伤后功能缺失的思路。     

酪氨酸蛋白激酶与突触可塑性及学习记忆的关系

近年来酪氨酸磷酸化在成年哺乳动物神经系统中的重要作用逐渐受到重视,酪氨酸蛋白激酶在调控与细胞增殖、分化、迁移及代谢相关的信号转导通路中起关键作用。本文主要对三种不同的酪氨酸蛋白激酶信号级联过程,即Trk受体酪氨酸激酶级联,Src家族非受体酪氨酸激酶级联及Eph受体酪氨酸激酶级联,以及它们在成年动物神经元突触可塑性及学习记忆形成过程中的重要作用及可能机制作一综述。     

受体酪氨酸激酶Eph基因表达与人类结直肠癌的研究进展

人类结直肠癌的发病是一个多因素、多步骤的渐进过程,促红细胞生成素产生肝细胞激酶（erythropoietin producing hepatocyte kinase,Eph）基因的异常表达在其中起着重要作用。Eph及其配体Ephrin具有重要的生理功能,近年来国内外的多项研究发现Eph家族的多个受体在大肠癌中具有异常表达,其异常表达与结直肠癌的浸润深度、分化程度及存活率密切相关,由此极大地扩展了对大肠癌发病机制的研究,为大肠癌的诊断和治疗提供了新的思路和手段。     

Mrg受体家族的研究进展

Mrg(mas related gene)受体家族是新发现的G蛋白偶联受体家族,特异性分布于感觉传入神经元上。研究发现Mrg受体家族参与了痛觉、免疫等生理病理过程;Mrg受体的内源性配体的寻找和构效关系研究对揭示此受体系统的生理学角色有重要意义;同时针对Mrg受体及其配体的药理学研究对于相关疾病的治疗提供了一个新靶点。     

SLC26蛋白家族成员功能及意义的研究进展

目前研究发现人类许多疾病与离子通道蛋白相关,故对于离子通道蛋白如何参与人类疾病的发展已成为各大学者的研究热点。 SLC26阴离子通道蛋白家族作为目前一类研究较多的离子通道蛋白,具有成员多、结构功能复杂多样等特点,可作为SO42-转运蛋白、阴离子交换器、阴离子通道蛋白等在组织上的特异性表达来发挥其功能,SLC26阴离子通道蛋白家族的表达及功能受多种机制调节,其家庭成员结构及功能变化与人类先天性营养不良、先天性氯化物腹泻、先天性耳聋及消化道疾病等多种人类疾病相关。本文就SLC26蛋白家族其结构功能、各家族成员及其主要功能、相关调节因素及其与相关疾病的关系等进行综述。     

选择蛋白及其配体与肿瘤转移

选择蛋白（selectin）是细胞黏附分子中的一个家族。包括3个成员：L-选择蛋白、P-选择蛋白和E-选择蛋白。选择蛋白分子具有糖链结合活性。能通过其分子中的凝集素样结构域与糖蛋白、糖脂或蛋白多糖上的糖配体（1igand）特异结合。在炎症发生时介导白细胞与血管内皮问的起始黏附．在淋巴组织中介导淋巴细胞的归巢．乃至在肿瘤的转移过程中发挥作用。另外。选择蛋白及其配体也可作为信号分子促进肿瘤的转移。因此，通过抑制选择蛋白与其配体的相互作用，或阻断选择蛋白的表达。可以作为防治肿瘤转移的一条重要思路。本研究就选择蛋白及其配体的分子结构、功能特点与肿瘤转移的相关性作一综述。     

NF-κB在细胞凋亡中调节作用的研究进展

细胞凋亡是由基因控制的细胞自主有序的主动死亡过程,主要有3条通路参与引起细胞凋亡,即细胞内的线粒体通路、内质网通路和细胞外的死亡受体通路。近年研究表明,NF-κB与细胞凋亡关系密切,具有抑制凋亡和促进凋亡的双向调节作用,其在细胞凋亡中调节作用与凋亡抑制蛋白家族、B细胞淋巴瘤/白血病-2家族、肿瘤坏死因子受体相关因子家族、c-Jun氨基端激酶、肿瘤坏死因子相关凋亡诱导配体和Fas相关死亡域蛋白样白细胞介素1β转化酶抑制蛋白等有关。探索NF-κB在细胞凋亡中的调控机制,对凋亡相关疾病的药物开发具有重要意义。本文就NF-κB在细胞凋亡中的调节作用进行综述。     

G蛋白偶联受体的二聚化及其意义

G蛋白偶联受体(G protein couple receptors,GPCRs)是一个超大的膜受体家族,可以被不同的配体所激活,如激素、多肽、氨基酸、光粒子等。通过与这些配体结合,它们可以介导许多的信号传导,通过激活细胞内的G蛋白,从而激活不同的细胞内通路,产生不同的生物学效应。在对GPCRs的研究初期,普遍认为它们是以单体形式存在并发挥作用的,但后来大量证据表明,绝大多数GPCRs存在二聚化甚至更高的聚合形式,并以此形成基本的功能单位。二聚化可以发生在同受体、相似家族受体或不同家族受体分子之间,其作用可以体现在受体信号传导通路中的诸多环节,如与配体的结合、受体的激活、失敏及运输等。     

趋化因子CXCL13及其受体CXCR5在疾病中的研究进展

趋化因子是一组小分子蛋白,属于细胞因子家族中作用于G蛋白偶联受体超家族的成员。趋化因子通过与其受体相互作用,发挥招募免疫细胞、活化淋巴细胞和激活炎症反应等功能。近年来,大量研究证明B淋巴细胞趋化因子-1(CXCL13)及其受体CXCR5与自身免疫病及肿瘤的生长、侵袭和转移等有关,此文综述CXCL13及其受体CXCR5相关疾病的研究进展。     

肿瘤坏死因子受体（TNFR）超家族三聚体

肿瘤坏死因子受体（TNFR）超家族的信号转导系统依赖于三聚配体复合物结构的形成，该复合物能激活受体，引起系列生化反应。复合物中几种TNF家族成员与其同源受体的结构表明，每种三聚配体与三种单体受体链相互作用。近期有文章分别报道了利用小分子激动剂和拮抗剂靶向作用于TNFR超家族成员的一种新方法。     

Eph receptor tyrosine kinases in tumor and tumor microenvironment

Eph receptors are a unique family of receptor tyrosine kinases (RTK) that play critical roles in embryonic patterning, neuronal targeting, and vascular development during embryogenesis. In adults, Eph RTKs and their ligands, the ephrins, are frequently overexpressed in a variety of cancers and tumor cell lines, including breast, prostate, non-small cell lung and colon cancers, melanomas, and neuroblastomas. Unlike traditional oncogenes that often function only in tumor cells, recent data show that Eph receptors mediate cell-cell interaction both in tumor cells and in tumor microenvironment, namely the tumor stroma and tumor vasculature. As such, Eph RTKs represent attractive potential targets for drug design, as targeting these molecules could attack several aspects of tumor progression simultaneously. This review will focus on recent advances in dissecting the role of Eph RTKs in tumor cells, tumor angiogenesis, and possible contribution to trafficking of inflammatory cells in cancer.     

Ephrins and pain

Introduction: The ephrin receptor family is the largest family of receptor tyrosine kinases, which comprises 14 members that are divided into A and B subclasses. The ephrin receptor (Eph-receptor) ligands are named ephrins. Ephrins/Eph receptors interact with a variety of membrane receptors that respond to chemokines, neurotransmitters or growth factors. A growing body of evidence indicates that ephrins/Eph receptors are involved in the modulation of different types of pain.

Areas covered: A literature review summarizing the most recent data in terms of ephrins and their ligands and their association with different types of pain. Moreover, the latest knowledge regarding the involvement of ephrins/Eph receptors in pain modulation as well as its possible therapeutic perspectives are presented.

Expert opinion: The ephrins/Eph receptors system seems to be an emerging target for pain drug discovery, because it is involved in the pathophysiology of many types of pain. The modulation of different types of pain by selective agonists or antagonists may hold tremendous therapeutic potential in various pain conditions mentioned in this review. However, the current limited but promising data, merit consideration and further investigation.     

EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics

Eph receptors are a unique family of receptor tyrosine kinases (RTK) that play critical roles in embryonic patterning, neuronal targeting, and vascular development during normal embryogenesis. Eph RTKs and their ligands, the ephrins, are also frequently overexpressed in a variety of cancers and tumor cell lines. In particular, one family member, EphA2, is overexpressed in breast, prostate, lung, and colon cancers. Unlike traditional oncogenes that often function only in tumor cells, recent data show that Eph receptors mediate cell-cell interactions both in tumor cells and in the tumor microenvironment, namely the tumor stroma and tumor vasculature. Thus, EphA2 receptors are attractive targets for drug design, as targeting these molecules could simultaneously inhibit several aspects of tumor progression. This review focuses on the multiple roles of EphA2 in cancer progression, the mechanisms by which EphA2 inhibition may halt this progression, and the pre-clinical results of EphA2 inhibition in various cancer model systems.     

An evolution of minimalist models for protein folding: from the behavior of protein-like polymers to protein function

This overview highlights several folding studies that have used simple models to describe specific proteins, beyond just the shared topology of a protein family. A shift in focus to specific proteins (rather than protein-like polymers) facilitates comparison to experiment, and more detailed models allow rationalization of specific experimental observations, and the suggestion of specific, testable predictions. This new class of models and their investigation opens the door to understanding the origins of folding behavior in the context of evolved structure and function.     

Growth factor receptors in hematopoietic stem cells: EPH family expression in CD34+ and CD133+ cell populations from mobilized peripheral blood

Cell-surface antigen expression of hematopoietic stem cells has a crucial role in characterizing cell subpopulation with distinct functional properties. The Eph receptors are the largest receptor tyrosine kinase family being involved in processes like vascular remodelling during development and physiological and pathological angiogenesis. Some Eph/Ephrin members are expressed in hematopoietic cells. The ability to isolate purified cell populations co-expressing CD34 and CD133 antigens as most commonly used markers for identification of hematopoietic progenitors has provided the opportunity to identify their surface-receptor profile. As positively expressed CD34 and CD133 cells take place not only in hematopoietic but also in endothelial differentiation, we aimed to define the Eph/Ephrin characteristic of these cells and relate these findings to new therapy strategies. Positive selections of CD34 and CD133 cells from PBPC in lymphoma patients were performed using magnetic beads and AutoMACS (Miltenyi Biotec) device. The purity of isolated cells was tested by flow cytometry. Immunocytochemistry was used to assess the Eph/Ephrin expression profile of positively selected samples. Our study revealed that all samples (10 from CD34+ and 8 from CD133+ cells) expressed one or more of Eph/Ephrin antigens in different proportions. All CD34+ cell samples, and 6 of 8 in the CD133+ cell fraction were strongly immunoreactive for EphA2. EphB2 was strongly expressed in all CD133+ cases, but 50% of the CD34 positive group lacked or weakly expressed this receptor. EphB4 was negative in 9 of 10 CD34+ cases and in all CD133+ cells. Thus, we have shown the surface marker profile of positively selected CD34 and CD133 cells in leukapheresis samples from lymphoma patients with regard to Eph/Ephrin receptors and discussed their biological clinical potential.     

Polyphenol rich botanicals used as food supplements interfere with EphA2–ephrinA1 system

The Eph tyrosine kinase receptors and their ephrin ligands play a central role in several human cancers and their deregulated expression or function promotes tumorigenesis, inducing aggressive tumor phenotypes. Green tea extracts (GTE) have been recently found to inhibit Eph-kinase phosphorylation. In order to evaluate the potential contribution of edible and medicinal plants on EphA2–ephrinA1 modulation, 133 commercially available plant extracts used as food supplements, essential and fixed oils were screened with an ELISA-based binding assay. Nine plant extracts, rich of polyphenols, reversibly inhibited binding in a dose-dependent manner (IC₅₀ 0.83–24 μg/ml). Functional studies on PC3 prostate adenocarcinoma cells revealed that active extracts antagonized ephrinA1-Fc-induced EphA2-phosphorylation at non-cytotoxic concentrations (IC₅₀ 0.31–11.3 μg/ml) without interfering with EGF-induced EGFR activation, suggesting a specific effect. These findings could furnish an interesting starting point regarding the potential relationship between diet, edible plant secondary metabolites and Eph–ephrin system, suggesting their possible involvement in cancer development modulation.     

A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors

Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid-furanyl derivative that inhibits ephrin-A5 binding to EphA4 with an IC(50) of 3 μm in ELISAs. This compound, which appears to bind to the ephrin-binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid-furanyl derivative inhibits EphA2 phosphorylation in response to TNFα and capillary-like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin-A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors.     

Eph/ephrin signalling and function in oncogenesis: lessons from embryonic development

Eph receptors and their membrane-bound ephrin ligands are developmental cell guidance cues that direct cell migration and orchestrate patterning processes by modulating adhesive or repulsive cell properties. During the past two decades, an exponentially growing interest in their function has resulted in a considerably advanced understanding of the cellular and molecular principles of Eph function in normal and oncogenic development. Ephs not only accurately guide the path of migrating cells, but also facilitate contact and communication between neighbouring cell populations, in particular at epithelial/mesenchymal boundaries. Precise cell positioning not only relies on accurately-graded expression of individual Eph/ephrin pairs, but on the sum of interactions within particular expression domains and their modulation through crosstalk with a range of other signalling systems. There is little doubt that Eph and ephrins provide exciting new targets for anti-cancer therapies, but in appreciation of the complexity of their signals and biological functions it is perhaps not surprising that the development of Eph-specific therapeutics is only emerging.     

Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer

Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the mkp-1 encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.     

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Abstract

GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.