Syndecans: transmembrane modulators of adhesion and matrix assembly
Syndecans: transmembrane modulators of adhesion and matrix assembly
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DOI：
10.1172/jci12802
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发表时间：
2001-04-01
影响因子：
15.9
通讯作者：
Woods, A
中科院分区：
文献类型：
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作者：
Woods, A
细胞生物学系，位于伯明翰的亚拉巴马大学，Volker Hall 203 A，1530 3rd Avenue S.，伯明翰，亚拉巴马35294-0019，美国。电话：（205）934-1548;传真：（205）975-9956;电子邮件：awoods@ cellbio。bhs.阿拉伯联合酋长国。edu.链长任何特定多配体蛋白聚糖的特异性GAG链的完全测序仍有待实现，但将产生极其重要的信息。多配体聚糖核心蛋白与其大的GAG链相比是小的（1-5）。这些蛋白质含有四个保守的酪氨酸残基，多配体蛋白聚糖可以被酪氨酸磷酸化，尽管所涉及的残基和这种修饰的生物学后果尚不清楚。它们的跨膜结构域是高度同源的，并且它们的短胞质尾区在膜的近端和远端具有高度同源性的两个区域（C1和C2），具有对单个多配体蛋白聚糖特异性的间插序列（V区）。这导致了这样的猜测，即某些功能是所有syndecans共有的，而其他功能则是个别家庭成员特有的。在共同的功能方面，所有的syndecan都有一个COOH末端的FYA序列，可以与含有PDZ结构域的蛋白质相互作用，这意味着在蛋白质-蛋白质相互作用中的作用。迄今为止，已经显示三种PDZ结构域蛋白与多配体蛋白聚糖相互作用（图1）：syntenin（8），CASK/LIN（9）和synectin（10）。此外，最近鉴定的结合配偶体synbindin（11）含有与PDZ结构域具有有限同源性的序列。最初，人们认为多配体蛋白聚糖与PDZ结构域蛋白的相互作用导致连接到细胞骨架的膜下支架的形成。然而，最近的证据指出这些多配体结合蛋白在蛋白质运输和/或分选到特定膜区域或从特定膜区域分选蛋白质中的可能作用（11-13）。特别是，这些蛋白质似乎可以调节多配体聚糖的聚集（11）。由于FYA基序对所有四种多配体蛋白聚糖都是共同的，因此可以预期可能发生一些结合竞争。然而，多配体蛋白聚糖在其表达中受到高度调节，无论是在发育中还是在细胞类型特异性方式中。通常，多配体蛋白聚糖-1是上皮细胞中的主要多配体蛋白聚糖，多配体蛋白聚糖-2是成纤维细胞中的主要多配体蛋白聚糖，多配体蛋白聚糖-3是神经元组织中的主要多配体蛋白聚糖，尽管在相同的细胞类型中可以表达多于一种多配体蛋白聚糖。有趣的是，syndecan-4虽然是一种次要成分，但存在于一系列细胞类型中，包括成纤维细胞、上皮细胞和平滑肌细胞，这可能表明这种跨膜蛋白聚糖的特定作用。多配体蛋白聚糖的C1结构域（图1）也是高度同源的。Syndecan-3通过其GAG链与肝素结合生长相关分子HB-GAM结合。结合导致轴突延伸，伴随着C1结构域与包括c-src和多配体蛋白聚糖-3底物coronin的复合物的相互作用（参考文献中综述）。第3-5段）。皮质激素与微丝膜下细胞骨架相互作用，并且可能间接地与微管系统相互作用。Ezrin是ERM（ezrin、radixin、膜突蛋白）家族的成员，结合多配体蛋白聚糖-2（14）。ERM蛋白也被假定为连接膜受体的皮质肌动蛋白网络。由于先前的研究表明，ERMs结合到跨膜蛋白的近膜碱性氨基酸序列，ezrin-syndecan-2的相互作用可能是通过C1结构域。同样，由于C1结构域是高度保守的，可以预期这种相互作用可能与其他多配体蛋白聚糖发生。第三种可以与C1区相互作用的蛋白质是韧带联合（syndesmos）（15）。Syndesmos结合syndecan-4的C1区域，但在这里...
Department of Cell Biology, University of Alabama at Birmingham, Volker Hall 203A, 1530 3rd Avenue S., Birmingham, Alabama 35294-0019, USA. Phone:(205) 934-1548; Fax:(205) 975-9956; E-mail: awoods@ cellbio. bhs. uab. edu. chain length. The complete sequencing of the specific GAG chains for any particular syndecan remains to be achieved but will yield extremely important information. Syndecan core proteins are small compared with their large GAG chains (1–5). These proteins contain four conserved tyrosine residues, and syndecans can be tyrosine phosphorylated, although the residues involved and the biological consequences of this modification are unclear. Their transmembrane domains are highly homologous, and their short cytoplasmic tails have two regions of high homology proximal and distal to the membrane (C1 and C2), with an intervening sequence (V region) that is specific to individual syndecans. This has led to the speculation that certain functions are common to all syndecans, with others specific for individual family members. In terms of common function, all syndecans have a COOH-terminal FYA sequence that can interact with PDZ domain containing proteins, which implies a role in protein-protein interactions. To date, three PDZ-domain proteins have been shown to interact with syndecans (Figure 1): syntenin (8), CASK/LIN (9), and synectin (10). In addition, a recently identified binding partner, synbindin (11), contains a sequence with limited homology to a PDZ domain. Initially it was thought that interactions of syndecans with PDZ domain proteins resulted in the formation of a submembraneous scaffold that connects to the cytoskeleton. However, recent evidence points to a possible role of these syndecan-binding proteins in trafficking and/or sorting of proteins to or from specific membrane areas (11–13). In particular, it appears these proteins may regulate clustering of syndecans (11). Since the FYA motif is common to all four syndecans, it might be expected that some competition for binding may occur. Syndecans, however, are highly regulated in their expression, both in development and in a cell type–specific manner. In general, syndecan-1 is the major syndecan in epithelial cells, syndecan-2 in fibroblasts, and syndecan-3 in neuronal tissue, although more than one syndecan can be expressed in the same cell type. Interestingly, syndecan-4, although a minor component, is present in a range of cell types, including fibroblasts, epithelial, and smooth muscle cells, perhaps indicating a specific role for this transmembrane proteoglycan. The C1 domains of syndecans (Figure 1) are also highly homologous. Syndecan-3 binds the heparin-binding growth-associated molecule HB-GAM via its GAG chains. Binding results in axonal extension, concomitant with an interaction of the C1 domain with a complex that includes c-src and the syndecan-3 substrate cortactin (reviewed in refs. 3–5). Cortactin interacts with the microfilament submembraneous cytoskeleton, and, perhaps indirectly, the microtubule system. Ezrin, a member of the ERM (ezrin, radixin, moesin) family, binds syndecan-2 (14). ERM proteins are also postulated to link membrane receptors to the cortical actin meshwork. Since previous studies indicate that ERMs bind to membrane-proximal basic amino acid sequences of transmembrane proteins, the ezrin-syndecan-2 interaction may be through the C1 domain. Again, since the C1 domains are highly conserved, it might be expected that this interaction could occur with the other syndecans. A third protein that can interact with a C1 region is syndesmos (15). Syndesmos binds the C1 region of syndecan-4, but here …