CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression.
CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression.
复制标题
DOI：
10.2741/a308
复制
发表时间：
1998-07
期刊：
影响因子：
--
通讯作者：
L. Bourguignon;D. Zhu;Hongbo Zhu
中科院分区：
文献类型：
--
作者：
L. Bourguignon;D. Zhu;Hongbo Zhu
CD44是一种主要的透明质酸受体，以多种亚型存在，广泛分布于不同的细胞和组织中。CD44的异构体，如CD44s(标准型)、CD44E(上皮型)和CD44v(变异型)(由1到10个(或11个)可变外显子的差异剪接而产生，这些外显子编码膜近端细胞外区的部分区域。CD44亚型的分子多样性由不同的生物合成过程和翻译后修饰[例如N-/O-糖基化或糖胺聚糖(GAG)加成]进一步复杂化。这种结构安排发生在变异区的不变区域或胞外区域，对于CD44介导的细胞外基质材料[ECM-透明质酸(HA)、胶原和纤维连接蛋白]与细胞内蛋白成分(如细胞骨架蛋白和各种调节酶)之间的通讯非常重要。位于CD44异构体胞质结构域的15个氨基酸序列[如NSGNGAVEDRKPSGL(人)或NGGNGTVEDRKPSEL(小鼠)]是该家族跨膜糖蛋白的骨架蛋白结合域。生化分析和体外诱变表明，CD44介导的“由外而内”和“由内而外”的细胞激活事件都需要锚蛋白结合域。此外，在致癌信号转导过程中，CD44s与细胞骨架的相互作用与信号转导分子(如p185HER2或Src激酶)紧密耦合。此外，CD44v亚型(CD44v10和CD44v3)与细胞骨架之间的跨膜连接可上调侵袭和转移特异性肿瘤表型[如基质降解(MMPs)活性、肿瘤细胞侵袭和迁移]。这些发现有力地表明，CD44亚型和细胞骨架之间的相互作用在肿瘤发生和肿瘤进展中起着关键作用。
CD44, a major hyaluronan receptor, exists as several isoforms and is widely distributed in different cells and tissues. The isoforms of CD44, such as CD44s (the standard form), CD44E (the epithelial form) and CD44v (variant isoforms) (arise from differential splicing of one to ten (or eleven) variable exons that encode portions of the membrane proximal extracellular domain. The molecular diversity of CD44 isoforms is further compounded by differential biosynthetic processes and post-translational modifications [e.g. N-/O-glycosylation or glycosaminoglycan (GAG) addition]. This structural arrangement, which occurs within either the invariant region or the extracellular domain of the variant region, is important for CD44-mediated communication between extracellular matrix materials [ECM-hyaluronic acid (HA), collagen and fibronectin] and intracellular protein components (e.g cytoskeletal proteins and various regulatory enzymes). The 15 amino acid sequence [e.g. NSGNGAVEDRKPSGL (in human) or NGGNGTVEDRKPSEL (in mouse)] residing in the cytoplasmic domain of CD44 isoforms is the ankyrin-binding domain of this family of transmembrane glycoproteins. Biochemical analyses plus in vitro mutagenesis indicate that the ankyrin-binding domain is required for CD44-mediated "outside-in" and "inside-out" cell activation events. Furthermore, CD44s-cytoskeleton interaction is tightly coupled with signal transducing molecules (e.g. p185HER2 or Src kinases) during oncogenic signaling. Moreover, the transmembrane linkage between CD44v isoforms (CD44v10 and CD44v3) and the cytoskeleton up-regulates invasive and metastatic-specific tumor phenotypes [e.g. matrix degradation (MMPs) activities, tumor cell invasion and migration]. These findings strongly suggest that the interaction between CD44 isoforms and the cytoskeleton plays a pivotal role in the onset of oncogenesis and tumor progression.