Sarcospan: a small protein with large potential for Duchenne muscular dystrophy.
Sarcospan: a small protein with large potential for Duchenne muscular dystrophy.
复制标题
DOI：
10.1186/2044-5040-3-1
复制
发表时间：
2013-01-03
期刊：
影响因子：
4.9
通讯作者：
Crosbie-Watson RH
中科院分区：
文献类型：
--
作者：
Marshall JL;Crosbie-Watson RH
与肌营养不良蛋白（Duchenne肌营养不良症的基因产物）相关的蛋白质的纯化导致了肌营养不良蛋白-糖蛋白复合物的发现。Sarcospan是一种25kda的跨膜蛋白，是最后一个被确定的成分，其在骨骼肌中的功能一直难以捉摸。这篇综述将集中在过去十年的进展，揭示肌张力是肌肉细胞粘附、力量和再生的重要调节因子。利用几种转基因小鼠模型进行的研究表明，在杜氏肌营养不良小鼠模型中过度表达肌跨可以改善病理并恢复肌细胞与层粘连蛋白的结合。肌张力提高了肌内三种主要层粘连蛋白结合复合物-肌营养不良蛋白复合物和肌营养不良蛋白糖蛋白复合物以及α7β1整合素的细胞表面表达。肌营养蛋白和α7β1整合素弥补了肌营养不良蛋白的缺失，并且发现肌筋膜在突触外肌膜增加了它们的丰度，这支持了肌筋膜作为治疗靶点的使用。在肌张力不足的小鼠中新发现的表型，包括膈肌的比力输出减少和力下降增加，是由肌营养蛋白和肌营养不良蛋白表达减少引起的，并进一步揭示了肌张力在决定这些复合物丰度中的作用。在sspn缺陷小鼠中，基因去除α7整合素（Itga7）后，肌营养不良蛋白水平和膈肌的比力输出进一步降低，这表明整合素和肌跨之间的相互作用对于维持肌营养不良蛋白-糖蛋白复合物和膈肌的力量产生至关重要。Sarcospan是Akt信号通路的主要调节因子，缺乏Sarcospan会显著损害肌肉再生，这一过程依赖于Akt的激活。有趣的是，sarcospan调节α-肌营养不良蛋白的一个特定亚群的糖基化，这是一种与肌营养不良蛋白和肌营养不良蛋白相关的层粘连蛋白结合受体，定位于神经肌肉连接处。对肌营养不良蛋白和肌营养蛋白糖蛋白复合物组装和运输到细胞表面的基本机制的了解尚不清楚，最近的研究表明，肌赘在这些基本过程中起作用。
Purification of the proteins associated with dystrophin, the gene product responsible for Duchenne muscular dystrophy, led to the discovery of the dystrophin-glycoprotein complex. Sarcospan, a 25-kDa transmembrane protein, was the last component to be identified and its function in skeletal muscle has been elusive. This review will focus on progress over the last decade revealing that sarcospan is an important regulator of muscle cell adhesion, strength, and regeneration. Investigations using several transgenic mouse models demonstrate that overexpression of sarcospan in the mouse model for Duchenne muscular dystrophy ameliorates pathology and restores muscle cell binding to laminin. Sarcospan improves cell surface expression of the dystrophin- and utrophin-glycoprotein complexes as well as α7β1 integrin, which are the three major laminin-binding complexes in muscle. Utrophin and α7β1 integrin compensate for the loss of dystrophin and the finding that sarcospan increases their abundance at the extra-synaptic sarcolemma supports the use of sarcospan as a therapeutic target. Newly discovered phenotypes in sarcospan-deficient mice, including a reduction in specific force output and increased drop in force in the diaphragm muscle, result from decreased utrophin and dystrophin expression and further reveal sarcospan’s role in determining abundance of these complexes. Dystrophin protein levels and the specific force output of the diaphragm muscle are further reduced upon genetic removal of α7 integrin (Itga7) in SSPN-deficient mice, demonstrating that interactions between integrin and sarcospan are critical for maintenance of the dystrophin-glycoprotein complex and force production of the diaphragm muscle. Sarcospan is a major regulator of Akt signaling pathways and sarcospan-deficiency significantly impairs muscle regeneration, a process that is dependent on Akt activation. Intriguingly, sarcospan regulates glycosylation of a specific subpopulation of α-dystroglycan, the laminin-binding receptor associated with dystrophin and utrophin, localized to the neuromuscular junction. Understanding the basic mechanisms responsible for assembly and trafficking of the dystrophin- and utrophin-glycoprotein complexes to the cell surface is lacking and recent studies suggest that sarcospan plays a role in these essential processes.
登录
查看更多内容
影响因子：
3.5
作者：
Di Certo, Maria Grazia;Corbi, Nicoletta;Passananti, Claudio
通讯作者：
Passananti, Claudio
影响因子：
4.8
作者：
Durbeej, M;Campbell, KP
通讯作者：
Campbell, KP
影响因子：
12.4
作者：
Deol, Jatinderpal R.;Danialou, Gawiyou;Karpati, George
通讯作者：
Karpati, George
影响因子：
2.9
作者：
O'Brien KF;Engle EC;Kunkel LM
通讯作者：
Kunkel LM
影响因子：
4.8
作者：
Crosbie, RH;Heighway, J;Campbell, KP
通讯作者：
Campbell, KP