Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells
Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells
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DOI：
10.1074/jbc.m410882200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Toole, BP
中科院分区：
文献类型：
--
作者：
Ghatak, S;Misra, S;Toole, BP
透明质酸在许多类型的人类癌症中富集，并且透明质酸表达或相互作用的操纵对动物模型中的肿瘤进展具有重大影响。ErbB 2活性增加是几种癌症的特征，并负责这些癌症中恶性细胞行为的许多方面。在这项研究中，我们表明，组成性高水平的活性，即自磷酸化，ErbB 2在HCT 116结肠癌细胞和TA 3/St乳腺癌细胞依赖于内源性透明质酸-CD 44相互作用。通过给予透明质酸低聚物、实验诱导的可溶性CD 44表达和CD 44表达的小干扰RNA敲低证实了对透明质酸-CD 44相互作用的依赖性。另一方面，通过过度表达透明质酸合成酶2或细胞外基质金属蛋白酶诱导因子来增加透明质酸的产生，导致MCF-7乳腺癌细胞中ErbB 2磷酸化水平升高，而MCF-7乳腺癌细胞通常表现出低水平的ErbB 2活性。此外，在HCT 116和TA 3/St细胞中，内源性透明质酸-CD 44相互作用的抑制导致组成性的、脂筏相关的信号传导复合物的分解，所述信号传导复合物含有磷酸化ErbB 2、CD 44、ezrin、磷酸肌醇3-激酶和伴侣分子Hsp 90和cdc 37。刺激MCF-7细胞中的透明质酸产生诱导该复合物的组装。我们的结论是，透明质酸调节ErbB 2的活性和它的相互作用与其他信号因子在癌细胞。
Hyaluronan is enriched in many types of human cancers, and manipulations of hyaluronan expression or interactions have a major influence on tumor progression in animal models. Increased ErbB2 activity is characteristic of several cancers and is responsible for many aspects of malignant cell behavior in these cancers. In this study we show that constitutively high levels of active, i.e. autophosphorylated, ErbB2 in HCT116 colon carcinoma cells and TA3/St mammary carcinoma cells are dependent on endogenous hyaluronan-CD44 interaction. Dependence on hyaluronan-CD44 interaction was demonstrated by the administration of hyaluronan oligomers, experimentally induced expression of soluble CD44, and small interfering RNA knockdown of CD44 expression. On the other hand, increasing hyaluronan production by overexpression of hyaluronan synthase 2 or emmprin causes elevated ErbB2 phosphorylation in MCF-7 mammary carcinoma cells, which normally exhibit low levels of ErbB2 activity. Furthermore, in HCT116 and TA3/St cells, inhibition of endogenous hyaluronan-CD44 interaction causes disassembly of a constitutive, lipid raft-associated, signaling complex containing phosphorylated ErbB2, CD44, ezrin, phosphoinositide 3-kinase, and the chaperone molecules, Hsp90 and cdc37. Stimulation of hyaluronan production in MCF-7 cells induces assembly of this complex. We conclude that hyaluronan regulates ErbB2 activity and its interactions with other signaling factors in carcinoma cells.