桥粒蛋白与离子转运相关通道

桥粒为细胞与细胞之间的一种连接结构,参与细胞间机械应力传导. 在心肌组织中,桥粒与粘着连接及缝隙连接共同构成闰盘,对于维护心肌闰盘结构和功能的完整性具有重要作用. 近年来,越来越多的研究表明,桥粒蛋白基因突变、表达的缺失或功能异常,可引起心肌细胞钠、钾离子通道、缝隙连接蛋白等心肌电活动相关结构的重塑,增加心肌电学异质性,进而促发心律失常. 本文将就桥粒蛋白与离子转运相关通道关系的最新研究进展进行综述.     

PNN促进肾癌的发展并抑制舒尼替尼诱导的细胞凋亡（英文）

桥粒相关蛋白与肿瘤的关系是目前的研究热点之一。传统观点认为,桥粒相关蛋白PNN(pinin)能够促进上皮细胞间的黏附和RNA的选择性剪接;而新近研究发现,PNN在肝癌、乳腺癌等肿瘤的发生发展中扮演着重要角色;但其是否参与肾透明细胞癌(ccRCC)的发生,尚需深入研究。在该研究中,首先发现PNN在肾癌组织和细胞中的表达显著性高于对照组;且其升高程度与肾癌的病理分级密切相关。其次,降低肾癌细胞中PNN的表达后,细胞增殖被显著抑制,细胞周期被阻滞在G_0/G_1期。最后,降低细胞内PNN的表达能显著增强靶向药物舒尼替尼的细胞毒性,增加凋亡细胞的数量,此作用与PI3K/AKT途径密切相关。因此,PNN能激活PI3K/AKT通路促进靶向药物舒尼替尼对肾癌细胞的毒性作用;PNN有望成为肾癌耐药靶向治疗的潜在靶点。     

γ—连环素及其研究进展

γ-连环素（γ-catenin,γ-cat)是实质细胞粘附连接处钙粘附素（cadherin,cd)/连环素复合体的胞内组成部分,同时还是桥粒的组成成份之一。近年发现,γ-cat同时还是一种癌基因,并参与wnt信号传导通路,介导粘附连接与桥粒之间的交流等。本文对γ-cat的生物学特性及其功能作一综述。     

黏附分子在肿瘤发生及发展中的作用

细胞黏附分子是以配体和受体相结合的形式,介导细胞与细胞间或细胞与基质间相互作用的一类分子,参与机体的多种重要生理和病理过程.近年来,在对肿瘤发生和发展的研究中发现,黏附分子可通过多种途径影响肿瘤的生长、浸润及转移过程.因此.对黏附分子在肿瘤发生和发展中作用及机制的深入研究,可为肿瘤早期诊断提供重要的分子指标和发现新的治疗靶标.并为进而形成临床诊疗新策略提供重要理论支持.现就几种重要黏附分子在肿瘤生长与转移中的作用进行综述.     

Vav3蛋白的调控机制及其生物学功能

Vav家族蛋白是Rho家族GTPase的鸟嘌呤核苷酸转移因子.Vav3作为Vav家族蛋白的成员之一,由8个结构域组成,其结构的复杂性赋予其功能的多样性.它可通过调节Rho家族不同成员的活性参与对MAPK、PI3K-Akt、NF-κB等信号转导通路的调控,在维持细胞形态、细胞黏附、血管生成、免疫功能的调节和细胞分化等过程中发挥重要作用.最近的研究发现,Vav3表达的失调与肿瘤发生密切相关,提示Vav3具有原癌基因的活性.本文对Vav3蛋白的结构、功能及其上下游的信号调节通路等进行了综述.     

半乳凝素-1的神经保护作用

半乳凝素-1(galectin-1)是半乳凝素家族成员之一,具有高度保守性,参与细胞生长、黏附、迁移以及肿瘤发生发展等过程.近年来研究还发现半乳凝素-1可能具有神经保护作用.     

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。     

tsRNA研究进展与展望

tRNA-derived small RNAs(tsRNA)是近年来发现的、存在于多种生物体内的一类非编码小RNA,来源于成熟tRNA或tRNA前体,其表达和修饰具有组织和细胞特异性. tsRNA参与应激反应、蛋白质翻译调控、核糖体生物合成、肿瘤发生、细胞增殖与凋亡、表观遗传信息的跨代传递等多种生理和病理过程. 本文主要对tsRNA的生成及分类、已知的生物学功能及作用机理、tsRNA 及其修饰在疾病中的作用等进行了综述.     

肿瘤相关糖基结合蛋白Galectin-3及其治疗性配体

糖类参与细胞间黏附、细胞与胞外基质黏附、细胞间特异性识别等过程.Galectin-3是哺乳动物体内存在的非酶类蛋白质,其结构上保守的碳水化合物识别结构域能优先与β-半乳糖苷类结构结合,参与生理生化反应.含有半乳糖苷或类似结构的物质,包括化学修饰糖类、功能多肽、天然改性糖类,作为galectin-3的配体,能不同程度地干预糖基和蛋白质的相互作用,抑制在肿瘤生长、侵袭和转移中具有重要作用的细胞间识别和黏附等过程.     

Ezrin蛋白的生物学作用及其与肿瘤转移的关系

Ezrin蛋白是ERM蛋白家族中的一员,最早被发现。人体几乎所有的组织细胞中都有Ezrin蛋白的存在。Ezrin蛋白分子通过磷酸化等方式来激活,暴露其分子上的功能位点,形成具有功能分子结构。亚细胞定位在胞浆中,细胞膜与骨架蛋白之间,通过链接细胞内骨架蛋白与膜蛋白来实现其多项复杂而又重要的功能。近年来发现Ezrin蛋白存在多种功能,包括参与细胞形态学、参与免疫突触的形成,与黏附分子作用进而来调节细胞与细胞或细胞与基质间的黏附、调节细胞运动性等。最重要的是它在多种肿瘤中高表达并促进肿瘤细胞的增殖及转移等活动,参与肿瘤的发生与发展。干扰肿瘤细胞内的Ezrin蛋白表达或抑制其磷酸化后,可以明显抑制肿瘤的转移。所以,Ezrin可能成为将来抑制肿瘤转移研究的潜在靶点。     

Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion

E-cadherin is a transmembrane glycoprotein that mediates calcium- dependent, homotypic cell-cell adhesion and plays an important role in maintaining the normal phenotype of epithelial cells. Disruption of E- cadherin activity in epithelial cells correlates with formation of metastatic tumors. Decreased adhesive function may be implemented in a number of ways including: (a) decreased expression of E-cadherin; (b) mutations in the gene encoding E-cadherin; or (c) mutations in the genes that encode the catenins, proteins that link the cadherins to the cytoskeleton and are essential for cadherin mediated cell-cell adhesion. In this study, we explored the possibility that inappropriate expression of a nonepithelial cadherin by an epithelial cell might also result in disruption of cell-cell adhesion. We showed that a squamous cell carcinoma-derived cell line expressed N-cadherin and displayed a scattered fibroblastic phenotype along with decreased expression of E- and P-cadherin. Transfection of this cell line with antisense N- cadherin resulted in reversion to a normal-appearing squamous epithelial cell with increased E- and P-cadherin expression. In addition, transfection of a normal-appearing squamous epithelial cell line with N-cadherin resulted in downregulation of both E- and P- cadherin and a scattered fibroblastic phenotype. In all cases, the levels of expression of N-cadherin and E-cadherin were inversely related to one another. In addition, we showed that some squamous cell carcinomas expressed N-cadherin in situ and those tumors expressing N- cadherin were invasive. These studies led us to propose a novel mechanism for tumorigenesis in squamous epithelial cells; i.e., inadvertent expression of a nonepithelial cadherin.     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.     

DLG5 in Cell Polarity Maintenance and Cancer Development

Failure in establishment and maintenance of epithelial cell polarity contributes to tumorigenesis. Loss of expression and function of cell polarity proteins is directly related to epithelial cell polarity maintenance. The polarity protein discs large homolog 5 (DLG5) belongs to a family of molecular scaffolding proteins called Membrane Associated Guanylate Kinases (MAGUKs). As the other family members, DLG5 contains the multi-PDZ, SH3 and GUK domains. DLG5 has evolved in the same manner as DLG1 and ZO1, two well-studied MAGUKs proteins. Just like DLG1 and ZO1, DLG5 plays a role in cell migration, cell adhesion, precursor cell division, cell proliferation, epithelial cell polarity maintenance, and transmission of extracellular signals to the membrane and cytoskeleton. Since the roles of DLG5 in inflammatory bowel disease (IBD) and Crohn''s disease (CD) have been reviewed, here, our review focuses on the roles of DLG5 in epithelial cell polarity maintenance and cancer development.     

EPITHELIAL CELL MIGRATION IN THE INTESTINE

Despite significant advances in our understanding of the roles of the cytoskeleton and matrix receptors in cell locomotion, derived largely fromin vitrostudies on the movement of epithelial cell sheets and isolated cells, the mechanism of epithelial cell migration in the adult intestine remains an enigma. The primary function of the epithelial cell cytoskeleton seems to be in the maintenance of the apical region of the epithelium facing the gut lumen. There we find the brush border, with its associated enzymes, and the intercellular adhesion complexes that give the epithelium its cohesiveness and its barrier function. Curiously, there is little in the way of an organized cytoskeleton in the basal region of the epithelium adjacent to the basement membrane on which the epithelium is presumed to migrate. In this short review, I focus on what is known about epithelial migration from our understanding of the structure of the epithelium and from studies on wound healing, and indicate some avenues for future study.     

Trask phosphorylation defines the reverse mode of a phosphotyrosine signaling switch that underlies cell anchorage state <link href="file

Phosphotyrosine signaling in anchored epithelial cells constitutes a spacially ordained signaling program that largely functions to promote integrin-linked focal adhesion complexes, serving to secure cell anchorage to matrix and as a bidirectional signaling hub that coordinates the physical state of the cell and its environment with cellular functions including proliferation and survival. Cells release their adhesions during processes such as mitosis, migration, or tumorigenesis, but the fate of signaling through tyrosine phosphorylation in unanchored cells remains poorly understood. In an examination of epithelial cells in the unanchored state, we find abundant phosphotyrosine signaling, largely recommitted to an anti-adhesive function mediated through the Src family phosphorylation of their transmembrane substrate Trask/CDCP1/gp140. Src-Trask phosphorylation inhibits integrin clustering and focal adhesion assembly and signaling, defining an active phosphotyrosine signaling program underlying the unanchored state. Src-Trask signaling and Src-focal adhesion signaling inactivate each other, constituting two opposing modes of phosphotyrosine signaling that define a switch underline cell anchorage state. Src kinases are prominent drivers of both signaling modes, identifying their position at the helm of adhesion signaling capable of specifying anchorage state through substrate selection. These experimental studies along with concurring phylogenetic evidence suggest that phosphorylation on tyrosine is a signaling function fundamentally linked with the regulation of integrins.     

Trask phosphorylation defines the reverse mode of a phosphotyrosine signaling switch that underlies cell anchorage state

Phosphotyrosine signaling in anchored epithelial cells constitutes a spacially ordained signaling program that largely functions to promote integrin-linked focal adhesion complexes, serving to secure cell anchorage to matrix and as a bidirectional signaling hub that coordinates the physical state of the cell and its environment with cellular functions including proliferation and survival. Cells release their adhesions during processes such as mitosis, migration or tumorigenesis, but the fate of signaling through tyrosine phosphorylation in unanchored cells remains poorly understood. In an examination of epithelial cells in the unanchored state, we find abundant phosphotyrosine signaling, largely recommitted to an anti-adhesive function mediated through the Src family phosphorylation of their transmembrane substrate Trask/CDCP1/gp140. Src-Trask phosphorylation inhibits integrin clustering and focal adhesion assembly and signaling, defining an active phosphotyrosine signaling program underlying the unanchored state. Src-Trask signaling and Src-focal adhesion signaling inactivate each other, constituting two opposing modes of phosphotyrosine signaling that define a switch underline cell anchorage state. Src kinases are prominent drivers of both signaling modes, identifying their position at the helm of adhesion signaling capable of specifying anchorage state through substrate selection. These experimental studies along with concurring phylogenetic evidence suggest that phosphorylation on tyrosine is a signaling function fundamentally linked with the regulation of integrins.Key words: Trask, CDCP1, gp140, tyrosine phosphorylation, integrin, Src     

Phosphorylation of VASP by AMPK alters actin binding and occurs at a novel site

Vasodilator-stimulated phosphoprotein (VASP) is an actin regulatory protein that functions in adhesion and migration. In epithelial cells, VASP participates in cell–cell adhesion. At the molecular level, VASP drives actin bundling and polymerization. VASP activity is primarily regulated by phosphorylation. Three physiologically relevant phosphorylation sites significantly reduce actin regulatory activity and are targeted by several kinases, most notable Abl and protein kinases A and G (PKA and PKG). AMP-dependent kinase (AMPK) is best characterized as a cellular sensor of ATP depletion, but also alters actin dynamics in epithelial cells and participates in cell polarity pathways downstream of LKB1. While little is known about how AMPK direct changes in actin dynamics, AMPK has been shown to phosphorylate VASP at one of these three well-characterized PKA/PKG phosphorylation sites. Here we show that phosphorylation of VASP by AMPK occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of AMPK activity results in the accumulation of VASP at cell–cell adhesions and a concomitant increase in cell–cell adhesion.     

Cytoskeletal mechanics during Shigella invasion and dissemination in epithelial cells

The actin cytoskeleton is key to the barrier function of epithelial cells, by permitting the establishment and maintenance of cell–cell junctions and cell adhesion to the basal matrix. Actin exists under monomeric and polymerized filamentous form and its polymerization following activation of nucleation promoting factors generates pushing forces, required to propel intracellular microorganisms in the host cell cytosol or for the formation of cell extensions that engulf bacteria. Actin filaments can associate with adhesion receptors at the plasma membrane via cytoskeletal linkers. Membrane anchored to actin filaments are then subjected to the retrograde flow that may pull membrane‐bound bacteria inside the cell. To induce its internalization by normally non‐phagocytic cells, bacteria need to establish adhesive contacts and trick the cell into apply pulling forces, and/or to generate protrusive forces that deform the membrane surrounding its contact site. In this review, we will focus on recent findings on actin cytoskeleton reorganization within epithelial cells during invasion and cell‐to‐cell spreading by the enteroinvasive pathogen Shigella, the causative agent of bacillary dysentery.     

Crossroads of integrins and cadherins in epithelia and stroma remodeling

Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis.     

Crossroads of integrins and cadherins in epithelia and stroma remodeling

Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis.