Tetraspanin CD82 represses Sp1-mediated Snail expression and the resultant E-cadherin expression interrupts nuclear signaling of β-catenin by increasing its membrane localization

• Published in: Cellular signalling 2018-12, Vol.52, p.83-94
• Main Authors: Lee, Moon-Sung, Byun, Hee-Jung, Lee, Jaeseob, Jeoung, Doo-Il, Kim, Young-Myeong, Lee, Hansoo
• Format: Article
• Language: English
• Subjects: Antigens, CD - metabolism; beta Catenin - metabolism; Cadherins - metabolism; CD82; Cell Adhesion; Cell Line, Tumor; E-cadherin; Fibronectins - metabolism; Humans; Integrins - metabolism; Kangai-1 Protein - physiology; Male; Prostatic Neoplasms - metabolism; Snail; Snail Family Transcription Factors - metabolism; Sp1; Sp1 Transcription Factor - metabolism; Wnt Signaling Pathway; β-catenin
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2018.09.001

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. •CD82 upregulates E-cadherin expression by repressing Sp1-mediated Snail expression.•CD82 suppresses the fibronectin-integrin signaling that induces Sp1 phosphorylation.•CD82-induced E-cadherin expression increases homotypic adhesion of epithelial cells.•E-cadherin upregulated by CD82 obstructs the nuclear translocation of β-catenin.