Department of Biomedical and Molecular Sciences, Pathology and Molecular Medicine, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada.
Department of Biomedical and Molecular Sciences, Pathology and Molecular Medicine, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):794-802. doi: 10.1016/j.bbamcr.2018.02.004. Epub 2018 Feb 16.
Caveolin-1 (Cav1) is an integral plasma membrane protein and a complex regulator of signal transduction. The Signal Transducer and Activator of Transcription-3 (Stat3) is activated by a number of receptor and non-receptor tyrosine kinases and is positively implicated in cancer. Despite extensive efforts, the relationship between Cav1 and Stat3 has been a matter of controversy. We previously demonstrated that engagement of E- or N-cadherin or cadherin-11 cell to cell adhesion molecules, as occurs with confluence of cultured cells, triggers a dramatic increase in the levels of tyr705 phosphorylated i.e. activated Stat3, by a mechanism requiring the cRac1 small GTPase. Since confluence was not taken into account in previous studies, we revisited the question of the relationship between Cav1 and Stat3-ptyr705 in non-transformed mouse fibroblasts and in human lung carcinoma cells, by examining their effect at different cell densities. Our results unequivocally demonstrate that Cav1 downregulates cadherin-11, by a mechanism which requires the Cav1 scaffolding domain. This cadherin-11 downregulation, in turn, leads to a reduction in cRac1 and Stat3 activity levels. Furthermore, in a feedback loop possibly through p53 upregulation, Stat3 downregulation increases Cav1 levels. Our data reveal the presence of a potent, negative regulatory loop between Cav1 and cadherin-11/Stat3, leading to Stat3 inhibition and apoptosis.
窖蛋白-1（Cav1）是一种完整的质膜蛋白，也是信号转导的复杂调节剂。信号转导子和转录激活子-3（Stat3）被许多受体和非受体酪氨酸激酶激活，并与癌症密切相关。尽管进行了广泛的研究，但 Cav1 和 Stat3 之间的关系一直存在争议。我们之前的研究表明，E-或 N-钙粘蛋白或钙粘蛋白-11 细胞间黏附分子的结合，如培养细胞汇合时发生的那样，通过需要 cRac1 小 GTP 酶的机制，触发 tyr705 磷酸化即激活 Stat3 的水平显著增加。由于之前的研究没有考虑到汇合，我们重新研究了 Cav1 和 Stat3-ptyr705 在非转化的小鼠成纤维细胞和人肺癌细胞中的关系，通过检查它们在不同细胞密度下的作用。我们的结果明确表明，Cav1 通过需要 Cav1 支架结构域的机制下调钙粘蛋白-11。这种钙粘蛋白-11 的下调反过来又导致 cRac1 和 Stat3 活性水平降低。此外，在可能通过 p53 上调的反馈回路中，Stat3 下调增加了 Cav1 水平。我们的数据揭示了 Cav1 和钙粘蛋白-11/Stat3 之间存在一种强大的负反馈调节环，导致 Stat3 抑制和细胞凋亡。
