Cytoskeleton and mechanical signal transduction

doi:10.3969/j.issn.2095-4344.2014.07.021

Abstract

Abstract:

BACKGROUND: Cells under mechanical stimulation can achieve their biological functions by converting mechanical signals into chemical signals through certain signal transduction mechanism. As the fibrous framework throughout a cell, cytoskeleton is one of the critical components in this process.
OBJECTIVE: Through systemically analyzing the role of the cytoskeleton in mechanical signal transduction, to provide a potential therapeutic target for the clinical treatment of cytoskeleton related diseases.
METHODS: In order to search relevant articles about the mechanics mechanism of signal transduction of cytoskeleton from PubMed and CNKI databases (from 1990 to 2012), a computer-based search was performed, using the key words of “cytoskeleton, microtubules, microfilaments, intermediate filaments, mechanical stimulation, signal transduction” in English and Chinese, respectively. After eliminating literatures which were irrelevant to research purpose or containing a similar content, 48 articles were chosen for further analysis.
RESULTS AND CONCLUSION: Mechanical stimulation plays an important role in cell proliferation, development and apoptosis. With the gradual understanding of the biological function of cytoskeleton, people have found that cytoskeleton is one of the critical components in the process of the mechanical signal transduction. After getting mechanical stimulation, cytoskeleton can be reorganized through Rho, protein kinase C, integrin and mitogen-activated protein kinase signaling pathways, then converting the mechanical stimulation to chemical signals and finishing its biological functions finally.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: cytoskeleton, signal transduction, Rho-associated kinases, protein kinase C, integrins, mitogen-activated protein kinases

CLC Number:

R318

Yao Yi-cun, Liang Wei-guo, Ye Dong-ping. Cytoskeleton and mechanical signal transduction[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(7): 1109-1114.

Figures/Tables 1

2.1 细胞骨架 2.1.1 细胞骨架的组成细胞骨架(cytoskeleton，CSK)是位于细胞膜内侧面的蛋白质纤维网架系统。广义的细胞骨架包括细胞外基质、细胞膜骨架、细胞质骨架和细胞核骨架，它们在结构上相互连接，形成贯穿于细胞的网架体系。人们通常所说的细胞骨架主要是指细胞质骨架，主要由微管、微丝和粗细介于两者之间中间丝组成。其中，微管主要是由微管蛋白(tubulin)组装而成的直径约为24 nm的细长中空圆管状结构；微丝，又称肌动蛋白纤维，主要由肌动蛋白组装而成的直径为7 nm的丝状结构；中间丝是粗细介于微管和微丝之间的绳索状结构，其成分复杂，类型多样。除此之外，细胞骨架还包含一些与其分布和功能发挥相关的细胞骨架结合蛋白，如微管相关蛋白(MAPs)、马达蛋白(motor protein)等。 2.1.2 细胞骨架的功能细胞骨架的3种成分在形态上、功能上虽有差异，但3者在空间上相互联系，功能上相互配合，构成了贯穿整个细胞的复杂骨架系统，决定了细胞的形态和功能。其主要功能可归结为以下几点：①结构支持作用。维持细胞的形态以及各种细胞器的定位。②参与细胞内各种细胞器、生物大分子的运输和信号传导。③作为细胞的动力装置参与保持细胞分裂、细胞迁移等在内的各种细胞运动。 2.2 细胞骨架相关力学信号通路对于生物力学信号在细胞内传递的化学途径，目前国内外学者主要认为有Rho家族、蛋白激酶C、整合素、丝裂霉素激活的蛋白激酶( MAPK)、Ca2+通道、细胞因子、一氧化氮(NO)途径等。 2.2.1 Rho家族 Rho蛋白家族是Ras超家族成员[1]，为一类小分子G蛋白( Small G protein，又称GTP ase，即GTP酶) 。到目前为止，已发现包括Rho、Rac 和Cdc42在内的三个亚家族共十余种。Rho蛋白具有GTP酶活性，是细胞内信号传导的重要枢纽，能快速转换于GTP结合的活化状态和GDP结合的非活化状态之间，将细胞外信号传至细胞内，发挥着“分子信号开关”作用。 Rho：研究表明，Rho在细胞应力纤维装配和黏附斑信号传导过程中处于中心地位[2-5]。其中最为关键的两个下游效应蛋白分子为Rho相关激酶ROCK及形成素相关蛋白mDia[6]。 ROCK是以一种GTP依赖的方式与Rho蛋白相互作用的激酶，结合Rho-GTP后其活性会增加，当其在细胞中过表达时，可以不依赖于Rho蛋白而诱导应力纤维的产生。ROCK激活会在细胞中央产生典型星状的粗大应力纤维，在应力纤维的组装中起主要作用。 ROCK可通过抑制肌球蛋白轻链(myosin light chain，MLC)磷酸酶活性，提高MLC磷酸化水平，激活肌球蛋白。还可以不依赖于钙调蛋白直接磷酸化MLC，激活肌球蛋白[7-9]。另外，cofilin是一种肌动蛋白结合蛋白，可以促进F-actin解聚，活化的ROCK可通过磷酸化LIM激酶抑制cofilin作用，维持肌动蛋白的聚合状态[10-11]。 mDia可以促进非肌球蛋白Ⅱ驱使下的肌动蛋白的收缩，mDia还可参与调节微管的组装和动态平衡[12-13]，表达高活性mDia的细胞，其微管的正负两端均处于稳固状态，产生平行的纤细应力纤维，且正极与黏附斑的锚定得以加强，该过程可能导致黏附斑的下调。以上均提示活化的Rho是通过肌球蛋白的收缩驱使应力纤维及黏附斑的形成。 Rac：Rac主要参与片状伪足的形成[14]。RacSH3区与波形蛋白WAVE结合后，能激活actin相关蛋白——Arp2/3复合体，Rac使质膜的肌动蛋白丝脱帽(uncapping)，从而促进肌动蛋白聚合[15]；另外，Rac还可通过下游靶分子PAK激活LIMK，进而磷酸化并失活cofilin，抑制肌动蛋白丝的解聚。 Cdc42：Cdc42称为细胞分裂周期蛋白42(cell division cycle 42)，对丝状伪足的产生有重要的调控作用。Cdc42蛋白激活肌动蛋白结合蛋白p56PAK蛋白激酶，使与其结合的肌动蛋白发生重排[16]。Cdc42通过激活WASP蛋白(Wiskott-Aldrich syndrome protein)激活Arp2/3复合物，促进肌动蛋白聚合[17]。另外，与Ras相似，Cdc42还能通过其下游靶蛋白PAK激活LIMK，从而使cofilin失活，维持肌动蛋白的聚合[18]。综上所述，Rho GTP ases在生物力学刺激下可通过多种途径调节细胞骨架结构和功能，在生物力学的信号传导中起重要作用。借此，Rho对细胞骨架的成分进行调节、对细胞-基质黏附及基质重塑产生影响，在细胞迁移、基因转录、细胞周期调控、膜泡运输中起重要作用，对椎间盘退变、胃黏膜的保护、肿瘤细胞转移等方面有着重要的影响。 2.2.2 蛋白激酶C(PKC) 蛋白激酶C属于肌醇磷脂依赖性丝/苏氨酸激酶家族，作为一种重要的蛋白激酶和细胞内信号分子，可作用于多种底物蛋白。目前已发现蛋白激酶C有12种亚型，根据分子结构将其分为经典型蛋白激酶C(conventional PKCs，cPKCs)、新型蛋白激酶C(novel PKCs，nPKCs)和非典型蛋白激酶C(atypical PKCs，aPKCs)。表1为蛋白激酶C的不同亚型及其在细胞内的不同定位。与蛋白激酶C共存的细胞骨架蛋白往往就是蛋白激酶C的靶底物，蛋白激酶C的激活可以直接引起该骨架蛋白的磷酸化，进而调节该细胞骨架蛋白的功能，蛋白激酶C组织特异性决定其在细胞骨架调节中的不同作用[19-20]。"

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