Regulated clustering of variant CD44 proteins increases their hyaluronate binding capacity.
Regulated clustering of variant CD44 proteins increases their hyaluronate binding capacity.
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DOI：
10.1083/jcb.135.4.1139
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发表时间：
1996-11
期刊：
影响因子：
--
通讯作者：
Ponta H
中科院分区：
文献类型：
--
作者：
Sleeman J;Rudy W;Hofmann M;Moll J;Herrlich P;Ponta H
细胞与细胞外基质成分透明质酸（HA）的接触在许多发育、生理和病理过程中发挥着重要作用，尽管人们对这种接触的调节知之甚少。 CD44 蛋白携带介导 HA 亲和力的氨基酸基序。 CD44 的最小 85-kD 同种型 (CD44) 的人工聚类先前已被证明可促进蛋白质与可溶性 HA 的结合 (Lesley, J.、R. Hyman 和 P.W. Kincade. 1993. Adv.Immunol. 54:271-335 ；Persche, A.、J. Lesley、N. English、I. Trowbridge 和 R. Hyman。 1995.欧洲免疫学杂志25：495-501）。在这里，我们表明，在大鼠胰腺癌细胞中，CD44 (CD44v) 的剪接变体，而不是 CD44s，在质膜中形成分子聚集体。我们证明了 CD44v 发生了还原敏感的二聚化，并且可以通过化学交联来稳定蛋白质的较大聚集。同一细胞上存在的不同 CD44v 蛋白专门形成同聚体。分子聚类不需要蛋白质的完整胞质结构域。 CD44v4-v7 的异位表达使细胞与可溶性 HA 结合的能力上调超过一个数量级，但仅当 CD44v4-v7 蛋白形成分子间聚集体时才如此。衣霉素治疗可抑制 CD44v 与 HA 的结合，同时破坏寡聚化。我们提出，由变异外显子的存在和糖基化等因素介导的 CD44 聚类调节，使细胞能够调节其 HA 结合特性。
Cell contact with the extracellular matrix component hyaluronic acid (HA) plays an important role in many developmental, physiological, and pathological processes, although the regulation of this contact is poorly understood. CD44 proteins carry an amino acid motif that mediates affinity to HA. Artificial clustering of the smallest 85-kD isoform of CD44 (CD44s) has previously been shown to promote binding of the protein to soluble HA (Lesley, J., R. Hyman, and P.W. Kincade. 1993. Adv. Immunol. 54:271-335; Persche, A., J. Lesley, N. English, I. Trowbridge, and R. Hyman. 1995. Eur. J. Immunol. 25:495-501). Here we show that in rat pancreatic carcinoma cells, splice variants of CD44 (CD44v), but not CD44s, form molecular aggregates in the plasma membrane. We demonstrate that reduction-sensitive dimerization of CD44v occurs, and also that larger aggregations of the protein can be stabilized by chemical cross-linking. Different CD44v proteins present on the same cell exclusively form homoaggregates. Molecular clustering does not require an intact cytoplasmic domain of the protein. The ability of cells to bind to soluble HA is upregulated more than one magnitude by the ectopic expression of CD44v4-v7, but only when the CD44v4-v7 protein forms intermolecular aggregates. Tunicamycin treatment inhibits HA binding by CD44v and at the same time destroys oligomerization. We propose that the regulation of clustering of CD44, mediated by factors including the presence of variant exons and glycosylation, allows cells in turn to regulate their HA binding properties.