The CD9/CD81 tetraspanin complex and tetraspanin CD151 regulate α3β1 integrin-dependent tumor cell behaviors by overlapping but distinct mechanisms.
The CD9/CD81 tetraspanin complex and tetraspanin CD151 regulate α3β1 integrin-dependent tumor cell behaviors by overlapping but distinct mechanisms.
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DOI：
10.1371/journal.pone.0061834
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Stipp CS
中科院分区：
文献类型：
--
作者：
Gustafson-Wagner E;Stipp CS
整合素α3β1在其配体层粘连蛋白332和层粘连蛋白511上有效地促进细胞运动，这可能有助于解释为什么α3β1一再与乳腺癌进展和转移有关。α3β1的促迁移功能强烈依赖于与细胞表面四跨膜蛋白的侧向相互作用。四跨膜蛋白CD 151直接与α3整联蛋白亚基相互作用，并将α3β1整联蛋白连接到其他四跨膜蛋白，包括CD 9和CD 81。CD 151的缺失破坏了α3β1与其他四跨膜蛋白的结合，并损害了α3β1依赖性运动。然而，对于特异性α3β1功能，除了CD 151之外的四跨膜蛋白的需求程度尚不清楚。为了开始阐明α3β1功能的哪些方面需要哪些四跨膜蛋白，我们通过RNA干扰创建了CD 9和CD 81缺失的乳腺癌细胞。需要沉默这两种密切相关的四跨膜蛋白以揭示它们对α3β1功能的贡献。然后，我们直接将我们的CD 9/CD 81沉默细胞与CD 151沉默细胞进行比较。CD 9/CD 81沉默的细胞和CD 151沉默的细胞均显示出层粘连蛋白-332上的延迟的α3β1依赖性细胞铺展。然而，令人惊讶的是，一旦完全扩散，CD 9/CD 81沉默细胞，而不是CD 151沉默细胞，表现出受损的α3β1依赖性定向运动和改变的前后细胞形态。同样出乎意料的是，需要CD 9/CD 81复合物（而不是CD 151）来促进乳腺癌细胞中α3β1与PKCα的结合，并且PKC抑制剂模拟了CD 9/CD 81沉默的细胞运动缺陷的方面。我们的数据揭示了特定的四跨膜蛋白对α3β1整联蛋白功能的重叠但令人惊讶的独特贡献。重要的是，某些CD 9/CD 81的α3β1调节功能可能不需要CD 9/CD 81通过CD 151与α3β1物理连接。
Integrin α3β1 potently promotes cell motility on its ligands, laminin-332 and laminin-511, and this may help to explain why α3β1 has repeatedly been linked to breast carcinoma progression and metastasis. The pro-migratory functions of α3β1 depend strongly on lateral interactions with cell surface tetraspanin proteins. Tetraspanin CD151 interacts directly with the α3 integrin subunit and links α3β1 integrin to other tetraspanins, including CD9 and CD81. Loss of CD151 disrupts α3β1 association with other tetraspanins and impairs α3β1-dependent motility. However, the extent to which tetraspanins other than CD151 are required for specific α3β1 functions is unclear. To begin to clarify which aspects of α3β1 function require which tetraspanins, we created breast carcinoma cells depleted of both CD9 and CD81 by RNA interference. Silencing both of these closely related tetraspanins was required to uncover their contributions to α3β1 function. We then directly compared our CD9/CD81-silenced cells to CD151-silenced cells. Both CD9/CD81-silenced cells and CD151-silenced cells showed delayed α3β1-dependent cell spreading on laminin-332. Surprisingly, however, once fully spread, CD9/CD81-silenced cells, but not CD151-silenced cells, displayed impaired α3β1-dependent directed motility and altered front-rear cell morphology. Also unexpectedly, the CD9/CD81 complex, but not CD151, was required to promote α3β1 association with PKCα in breast carcinoma cells, and a PKC inhibitor mimicked aspects of the CD9/CD81-silenced cell motility defect. Our data reveal overlapping, but surprisingly distinct contributions of specific tetraspanins to α3β1 integrin function. Importantly, some of CD9/CD81's α3β1 regulatory functions may not require CD9/CD81 to be physically linked to α3β1 by CD151.
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