Lin Jim Jung-Ching, Eppinga Robbin D, Warren Kerri S, McCrae Keith R
Department of Biology, University of Iowa, 340BBE, Iowa City, IA 52242-1324, USA.
Adv Exp Med Biol. 2008;644:201-22. doi: 10.1007/978-0-387-85766-4_16.
Over the past two decades, extensive molecular studies have identified multiple tropomyosin isoforms existing in all mammalian cells and tissues. In humans, tropomyosins are encoded by TPM1 (alpha-Tm, 15q22.1), TPM2 (beta-Tm, 9p13.2-p13.1), TPM3 (gamma-Tm, 1q21.2) and TPM4 (delta-Tm, 19p13.1) genes. Through the use of different promoters, alternatively spliced exons and different sites of poly(A) addition signals, at least 22 different tropomyosin cDNAs with full-length open reading frame have been cloned. Compelling evidence suggests that these isoforms play important determinants for actin cytoskeleton functions, such as intracellular vesicle movement, cell migration, cytokinesis, cell proliferation and apoptosis. In vitro biochemical studies and in vivo localization studies suggest that different tropomyosin isoforms have differences in their actin-binding properties and their effects on other actin-binding protein functions and thus, in their specification ofactin microfilaments. In this chapter, we will review what has been learned from experimental studies on human tropomyosin isoforms about the mechanisms for differential localization and functions of tropomyosin. First, we summarize current information concerning human tropomyosin isoforms and relate this to the functions of structural homologues in rodents. We will discuss general strategies for differential localization oftropomyosin isoforms, particularly focusing on differential protein turnover and differential isoform effects on other actin binding protein functions. We will then review tropomyosin functions in regulating cell motility and in modulating the anti-angiogenic activity of cleaved high molecular weight kininogen (HKa) and discuss future directions in this area.
在过去二十年中，广泛的分子研究已鉴定出存在于所有哺乳动物细胞和组织中的多种原肌球蛋白异构体。在人类中，原肌球蛋白由TPM1（α-Tm，15q22.1）、TPM2（β-Tm，9p13.2-p13.1）、TPM3（γ-Tm，1q21.2）和TPM4（δ-Tm，19p13.1）基因编码。通过使用不同的启动子、可变剪接外显子和不同的聚腺苷酸化信号位点，至少已克隆出22种具有全长开放阅读框的不同原肌球蛋白cDNA。有力证据表明，这些异构体是肌动蛋白细胞骨架功能的重要决定因素，如细胞内囊泡运动、细胞迁移、胞质分裂、细胞增殖和凋亡。体外生化研究和体内定位研究表明，不同的原肌球蛋白异构体在肌动蛋白结合特性以及对其他肌动蛋白结合蛋白功能的影响方面存在差异，因此在肌动蛋白微丝的特异性方面也存在差异。在本章中，我们将回顾从关于人类原肌球蛋白异构体的实验研究中学到的有关原肌球蛋白差异定位和功能机制的知识。首先，我们总结有关人类原肌球蛋白异构体的当前信息，并将其与啮齿动物中结构同源物的功能相关联。我们将讨论原肌球蛋白异构体差异定位的一般策略，特别关注差异蛋白质周转以及异构体对其他肌动蛋白结合蛋白功能的影响。然后，我们将回顾原肌球蛋白在调节细胞运动以及调节裂解的高分子量激肽原（HKa）的抗血管生成活性方面的功能，并讨论该领域的未来方向。
