Adan Hanad, Guy Stephanie, Arulanandam Rozanne, Geletu Mulu, Daniel Juliet, Raptis Leda
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
Department of Biology, McMaster University, Hamilton, ON, L8S 4L8, Canada.
Cancer Gene Ther. 2022 Oct;29(10):1502-1513. doi: 10.1038/s41417-022-00462-5. Epub 2022 Apr 11.
We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner. This results in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705, which then dimerizes, migrates to the nucleus, and activates transcription of genes involved in cell division and survival. In the present report we demonstrate that, in mouse Balb/c3T3 fibroblasts, mutationally activated Src also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. Interestingly, our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. At the same time, however, activated Src downregulates cadherin-11, in a quantitative manner. As a result, Src expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. However, expressed to high levels, Src eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation. This fine balance between Src and cadherin-11 levels which is required for Stat3 activation and cellular survival could have significant therapeutic implications.
我们之前证明，钙黏蛋白（细胞间黏附分子）的结合会引发Rac/Cdc42小GTP酶的水平和活性急剧增加，随后以自分泌方式分泌IL6家族细胞因子并激活其共同受体gp130。这导致信号转导子和转录激活子3（Stat3）的酪氨酸705位点发生磷酸化，然后二聚化，迁移至细胞核，并激活参与细胞分裂和存活的基因转录。在本报告中，我们证明，在小鼠Balb/c3T3成纤维细胞中，突变激活的Src也会增加Rac水平，导致IL6家族细胞因子的分泌和gp130的激活，进而引发Stat3-ptyr705的增加。有趣的是，我们的结果还表明，钙黏蛋白-11是维持IL6家族信号传导所需的gp130水平所必需的。然而，与此同时，激活的Src会定量下调钙黏蛋白-11。因此，将Src表达至中等水平可使钙黏蛋白-11充足，从而使gp130达到激活Stat3所需的水平，正如预期的那样。然而，当Src高水平表达时，会消除钙黏蛋白-11，从而消除gp130信号传导，进而消除Stat3-ptyr705的刺激。综上所述，这些数据首次确立了Src、钙黏蛋白-11、gp130和Stat3激活之间的循环。Src和钙黏蛋白-11水平之间的这种精细平衡是Stat3激活和细胞存活所必需的，可能具有重要的治疗意义。
