Tetraspanin membrane proteins form physical complexes with signaling molecules and have been suggested to influence the signaling events of associated molecules. Of the tetraspanin proteins, CD82 has been shown to promote homotypic cell-cell adhesion, which partially accounts for its role in suppressing cancer invasion and metastasis. We found here that CD82-induced cell-cell adhesion is attributed to increased E-cadherin expression through CD82-mediated downregulation of the E-cadherin repressor Snail. The Snail repression by CD82 resulted from the reduced binding of the Sp1 transcription factor to the Snail gene promoter. Notably, high CD82 expression did not allow the fibronectin matrix to induce Sp1 phosphorylation, implicating CD82 inhibition of the fibronectin-integrin signaling-dependent Sp1 activation. Meanwhile, E-cadherin upregulated by CD82 pulled β-catenin up to the membrane region, and consequently reduced the amount of cytoplasmic β-catenin that was able to move into to the nucleus. The Wnt signal-induced nuclear translocation of β-catenin was also inhibited by the CD82 function of upregulating E-cadherin. Overall, high CD82 expression was likely to suppress fibronectin adhesion-induced Sp1 activation signaling for Snail expression, resulting in continuous E-cadherin expression, which contributed not only to the maintenance of strong cell-cell adhesion but also to the blockage of nuclear β-catenin signaling.

四跨膜蛋白与信号分子形成物理复合物，并被认为会影响相关分子的信号事件。在四跨膜蛋白中，CD82已显示出促进同型细胞粘附，这部分解释了其在抑制癌症侵袭和转移中的作用。我们在这里发现CD82诱导的细胞粘附是通过CD82介导的E-cadherin阻遏物Snail的下调而增加的E-cadherin的表达。CD82抑制Snail的原因是Sp1转录因子与Snail基因启动子的结合减少。值得注意的是，高CD82表达不允许纤连蛋白基质诱导Sp1磷酸化，暗示CD82抑制纤连蛋白-整合素信号依赖性Sp1活化。同时，CD82上调的E-钙粘蛋白将β-catenin向上拉到膜区域，因此减少了能够进入细胞核的细胞质β-catenin的数量。Wnt信号诱导的β-catenin的核易位也受到上调E-cadherin的CD82功能的抑制。总体而言，高CD82表达可能会抑制纤连蛋白粘附诱导的Snail表达的Sp1激活信号传导，从而导致E-钙粘着蛋白持续表达，这不仅有助于维持强的细胞粘附性，还有助于阻止核β-连环蛋白信号传导。Wnt信号诱导的β-catenin的核易位也受到上调E-cadherin的CD82功能的抑制。总体而言，高CD82表达可能会抑制纤连蛋白粘附诱导的Snail表达的Sp1激活信号传导，从而导致E-钙粘着蛋白持续表达，这不仅有助于维持强的细胞粘附性，还有助于阻止核β-连环蛋白信号传导。Wnt信号诱导的β-catenin的核易位也受到上调E-cadherin的CD82功能的抑制。总体而言，高CD82表达可能会抑制纤连蛋白粘附诱导的Snail表达的Sp1激活信号传导，从而导致E-钙粘着蛋白持续表达，这不仅有助于维持强的细胞粘附性，还有助于阻止核β-连环蛋白信号传导。