文章：

四聚氰胺：抑制和促进转移的推拉作用

Tetraspanins: push and pull in suppressing and promoting metastasis

原文发布日期：2008-12-11

DOI: 10.1038/nrc2543

类型: Review Article

开放获取: 否

要点：

1. The tetraspanins are a family of proteins that cross the membrane four times and have a short amino- and carboxy-terminal tail, a small intracellular loop between transmembrane region 2 (TM2) and TM3, a small extracellular loop (ECL1) between TM1 and TM2 and a large extracellular loop (ECL2) between TM3 and TM4. Palmitoylation of intracellular, juxtamembrane cysteines is thought to be required for initiating tetraspanin–tetraspanin web formation.
2. Tetraspanins form complexes by interacting between themselves and with a variety of transmembrane and cytosolic proteins that are required for their function, including integrins, growth factor receptors, G-protein-coupled receptors and their intracellular associated heterotrimeric G-proteins, several peptidases, transmembrane proteins associated with tumour progression, immunoglobulin superfamily members and cytosolic signal transduction molecules.
3. Tetraspanins also associate with cholesterol and gangliosides, enabling higher order tetraspanin complexes to form in microdomains, termed tetraspanin-enriched membrane microdomains (TEMs), which provide a signalling platform. Although TEMs share several features with lipid rafts, they are independent and different from these structures.
4. Tetraspanins are abundant in membranes of various types of endocytic organelles and in exosomes — 30–100 nm vesicles that are released by many cells. Exosomes are thought to constitute a potent mode of intercellular communication that is also important in tumour progression.
5. Tetraspanins function by modulating, stabilizing or preventing the activities of their associated molecules, which vary depending on the composition of the TEM. Thus, tetraspanins can promote spreading and migration, which mostly rely on compartmentalization of integrins or integrin internalization and recycling or on modulating integrin signalling. However, tetraspanins can also be important in cell adhesion by regulating the trafficking and biosynthesis of associating integrins.
6. The tetraspanins CD82 and CD9 mostly suppress tumour progression. By their interactions with a variety of proteins including integrins, signalling proteins and immunoglobulin superfamily members they suppress motility and promote adherance to the surrounding matrix. Their expression is often reduced in late-stage human tumours.
7. Two tetraspanins, CD151 and tetraspanin 8 (D6.1A in rats), are overexpressed in several human tumours and seem to support tumour progression. CD151 regulates cell migration, mostly through its association with α3β1, α6β4 and matrix metalloproteinases. Additional transmembrane and cytosolic proteins in multimolecular complexes in TEM, contribute. Tetraspanin 8 regulates cell motility and survival and is involved in the promotion of angiogenesis.
8. The opposing effects of CD82 and CD9 versus CD15 and tetraspanin 8 on metastasis suppression and promotion cannot be fully explained by differences in the composition of the TEM. Indeed, there are strong hints that, by their enrichment in exosomes, tetraspanins and associated molecules become engaged in intercellular communication, where their involvement in membrane fusion facilitates message, including mRNA and microRNA, delivery.
9. A more comprehensive picture of the dynamics of TEM and the contribution of tetraspanins to exosome-meditated intercellular communication might allow us to therapeutically dictate the push and pull of tetraspanins in metastasis suppression.

要点翻译：

1. 四跨膜蛋白是一类四次跨膜蛋白家族，其结构特征包括：较短的氨基末端和羧基末端尾部、跨膜区2（TM2）与TM3之间形成小的胞内环、TM1与TM2之间形成小的胞外环（ECL1）以及TM3与TM4之间形成大的胞外环（ECL2）。胞内近膜区半胱氨酸的棕榈酰化修饰被认为是启动四跨膜蛋白-四跨膜蛋白网络形成的关键条件。
2. 四跨膜蛋白通过自身相互作用，并与多种跨膜蛋白和胞质蛋白（包括整合素、生长因子受体、G蛋白偶联受体及其胞内关联的异源三聚体G蛋白、多种肽酶、肿瘤进展相关跨膜蛋白、免疫球蛋白超家族成员以及胞质信号转导分子）形成复合物以执行功能。
3. 四跨膜蛋白还能与胆固醇和神经节苷脂结合，在微结构域（称为四跨膜蛋白富集膜微域，TEMs）中形成高级复合物，这些微域可作为信号转导平台。尽管TEMs与脂筏具有若干共同特征，但它们是独立且不同于脂筏的结构。
4. 四跨膜蛋白广泛存在于各类内吞细胞器膜及外泌体（许多细胞释放的30-100纳米囊泡）中。外泌体被认为是细胞间通讯的重要媒介，在肿瘤进展中发挥关键作用。
5. 四跨膜蛋白通过调节、稳定或抑制其关联分子的活性发挥功能，这些作用因TEM组成差异而不同。因此，四跨膜蛋白可促进细胞铺展和迁移——这些功能主要依赖于整合素的分区化、整合素的内化与循环利用，或通过调节整合素信号实现。此外，四跨膜蛋白还能通过调控相关整合素的运输和生物合成，在细胞黏附中起重要作用。
6. 四跨膜蛋白CD82和CD9主要抑制肿瘤进展。它们通过与整合素、信号蛋白及免疫球蛋白超家族成员等多种蛋白相互作用，抑制细胞运动并促进细胞与周围基质黏附。这两种蛋白在晚期人类肿瘤中的表达常显著降低。
7. 而四跨膜蛋白CD151与四跨膜蛋白8（大鼠中称为D6.1A）在多种人类肿瘤中过表达，似乎促进肿瘤进展。CD151主要通过与α3β1、α6β4及基质金属蛋白酶结合来调节细胞迁移。TEM多分子复合物中的其他跨膜蛋白和胞质蛋白也参与这一过程。四跨膜蛋白8则通过调节细胞运动性和存活，参与促进血管生成。
8. CD82、CD9与CD151、四跨膜蛋白8在转移抑制与促进方面的对立效应，无法完全用TEM组成差异来解释。现有强烈证据表明，四跨膜蛋白及其关联分子通过在外泌体中富集，参与细胞间通讯：其在膜融合过程中的介入促进了信使物质（包括mRNA和microRNA）的递送。
9. 更全面地认识TEM动态特性及四跨膜蛋白在外泌体介导的细胞间通讯中的作用，或能让我们通过治疗手段调控四跨膜蛋白在转移抑制中的双向调节作用。

英文摘要：

Tumours progress through a cascade of events that enable the formation of metastases. Some of the components that are required for this fatal process are well established. Tetraspanins, however, have only recently received attention as both metastasis suppressors and metastasis promoters. This late appreciation is probably due to their capacity to associate with various molecules, which they recruit into special membrane microdomains, and their abundant presence in tumour-derived small vesicles that aid intercellular communication. It is reasonable to assume that differences in the membrane and vesicular web components that associate with individual tetraspanins account for their differing abilities to promote and suppress metastasis.

摘要翻译： 

肿瘤通过一系列级联事件进展，从而形成转移。这一致命过程中所需的一些组分已得到充分确认。然而，四跨膜蛋白（Tetraspanins）直到最近才作为转移抑制因子和促进因子受到关注。这种迟来的重视可能源于它们能与多种分子结合，将其招募至特殊的膜微区，并大量存在于肿瘤来源的小囊泡中，协助细胞间通讯。可以合理推测，与不同四跨膜蛋白结合的膜及囊泡网络组分的差异，决定了它们在促进或抑制转移方面的不同能力。

原文链接：

Tetraspanins: push and pull in suppressing and promoting metastasis