Centre for Tumour Biology, The London School of Medicine and Dentistry, John Vane Science Centre, London, UK.
Oncogene. 2011 Mar 24;30(12):1422-35. doi: 10.1038/onc.2010.535. Epub 2010 Dec 6.
Expression of the integrin αvβ6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvβ6 composed of wild-type αv and a mutant β6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvβ6-dependent adhesion or migration, are essential for αvβ6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the β6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant β6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous β6 and colocalised with αvβ6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvβ6-dependent adhesion or migration but abrogated αvβ6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the β6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of β6, bound directly to recombinant Psor and inhibited cellular Psor binding to β6; this blocked αvβ6-dependent, but not αvβ6-independent, invasion. These data identify a novel interaction between Psor and β6 and demonstrate that it is required for αvβ6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion.
整合素 αvβ6 的表达在多种癌中上调，似乎参与了恶性进展，尽管这种整合素的生物学尚未完全探索。我们已经生成了表达由野生型 αv 和缺乏独特的 C 末端 11 个氨基酸 (aa) 的突变体 β6 组成的 αvβ6 的口腔癌细胞。我们发现这些残基虽然对于 αvβ6 依赖性粘附或迁移不是必需的，但对于 αvβ6 依赖性侵袭活性是必需的。我们使用蛋白质组学方法鉴定了 β6 亚基胞质尾的新结合伙伴，并报告角蛋白丝聚集蛋白 (Psor) (S100A7) 优先与重组 β6 胞质结构域结合，尽管不存在独特的 C 末端 11aa。内源性细胞 Psor 与内源性 β6 共沉淀，并与 αvβ6 在细胞膜和细胞内小泡上共定位。用小干扰 RNA 敲低 Psor 对 αvβ6 依赖性粘附或迁移没有影响，但在 Transwell 和更具生理相关性的器官样侵袭测定中，阻断了 αvβ6 介导的口腔癌细胞侵袭，重现了 β6 突变细胞系的行为。编码 β6 独特 C 末端残基的膜通透 Tat 肽直接与重组 Psor 结合，并抑制细胞内 Psor 与 β6 的结合；这阻断了 αvβ6 依赖性，但不阻断 αvβ6 非依赖性的侵袭。这些数据鉴定了 Psor 和 β6 之间的一种新相互作用，并证明它是癌细胞中 αvβ6 依赖性侵袭所必需的。抑制这种相互作用可能代表了一种针对癌侵袭的新型治疗策略。
