Src 通过 Cadherin-11 (CDH11)、RAC1 和 gp130 (IL6ST) 定量激活 STAT3
中文名称
通路描述
早期结果表明，突变激活的致癌鸡 SRC (SRC-Y527F) 激活 STAT3 并需要 STAT3 活性进行肿瘤转化 (Turkson et al. 1998, Bromberg et al. 1998)。关于机制，后来发现 SRC-Y527F 增加 RAC 水平，导致分泌 IL6，进而激活 STAT3。有趣的是，SRC-Y527F 还定量下调 Cadherins (CDH11 和 CDH1)，而 Cadherins 对于 IL6ST 的完整性以及 IL6 家族信号传导是必需的。因此，SRC-Y527F 表达至中等水平允许足够的 CDH11，从而维持 IL6ST 水平以激活 STAT3，如先前报道 (Turkson et al. 1998, Bromberg et al. 1998)。然而，表达至高水平时，SRC-Y527F 消除 CDH11，从而消除 IL6ST 信号传导，从而完全消除 p-Y705-STAT3。综合这些数据揭示了 SRC、CDH11、IL6/IL6ST 和 STAT3 之间的循环。SRC-Y527F 与 CDH11 水平之间的平衡，对于 STAT3 激活和细胞生存是必需的，导致在细胞中具有高鸡 SRC-Y527F 时，在 SRC 抑制下 p-Y705-STAT3 增加（而不是减少），这一发现对于激活 SRC 抑制剂的治疗具有重大意义 (Adan, Guy et al. 2022，参见 Adan et al. 2022)。值得注意的是，许多原癌基因，如小鼠多瘤病毒肿瘤抗原膜结合体，通过结合并增加细胞 SRC 的激酶活性而转化细胞 (Raptis et al. 1985)。此外，还证明核原癌基因如 SVLT (猴病毒 40 大肿瘤抗原) 也能激活 STAT3 (Vultur et al. 2005)，并且 SVLT 需要 c-SRC 进行原癌转化 (Arulanandam et al. 2010)。有趣的是，细胞 STAT3 抑制剂 Caveolin-1 (CAV1) 蛋白通过结合并锚定 Cadherins 到其支架结构域，减少 IL6ST 和 p-Y705-STAT3 (Geletu et al. 2018)。因此，看来通往 STAT3 的道路是“铺满 Cadherins”的，无论是增加还是减少 STAT3 活性 (参见 Adan et al. 2022)。
英文描述
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST) Early results demonstrated that mutationally activated, oncogenic chicken SRC (SRC-Y527F) activates STAT3 and requires STAT3 activity for neoplastic conversion (Turkson et al. 1998, Bromberg et al. 1998). Regarding the mechanism, it was later shown that SRC-Y527F increases RAC levels, leading to secretion of IL6, which leads to STAT3 activation. Interestingly however, SRC-Y527F also downregulates cadherins (CDH11 and CDH1), in a quantitative manner, while cadherins are required for the integrity of IL6ST for IL6 family signalling. As a result, SRC-Y527F expression to intermediate levels allows sufficient CDH11, hence IL6ST levels, for STAT3 activation, as previously reported (Turkson et al. 1998, Bromberg et al. 1998). However, expressed to high levels, SRC-Y527F eliminates CDH11, hence IL6ST signaling, thus eliminating p-Y705-STAT3 entirely.Taken together, these data reveal the existence of a loop between SRC, CDH11, IL6/IL6ST and STAT3. This fine balance between SRC-Y527F and CDH11 levels which is required for STAT3 activation and cellular survival, results in an increase (rather than a decrease) in p-Y705-STAT3 in cells with high-chicken SRC-Y527F upon SRC inhibition (Adan et al. 2022), a finding which could have significant therapeutic implications regarding inhibitors of activated SRC (Adan, Guy et al. 2022, reviewed in Adan et al. 2022).It is interesting to note that a number of oncogenes, such as the membrane-bound, middle Tumor Antigen of the mouse polyoma virus, transform cells through binding to and increasing the kinase activity of the cellular SRC (Raptis et al. 1985). In addition, it was also demonstrated that nuclear oncogenes such as SVLT (Simian Virus 40 Large Tumor antigen) are also able to activate STAT3 (Vultur et al. 2005), and that SVLT requires c-SRC for oncogenic transformation (Arulanandam et al. 2010).Interestingly, a cellular STAT3 inhibitor, the Caveolin-1 (CAV1) protein, reduces IL6ST and p-Y705-STAT3 by binding to and sequestering cadherins onto its scaffolding domain (Geletu et al. 2018). Therefore, it appears that the road to STAT3 is âpaved with cadherinsâ, either to increase, or to decrease, STAT3 activity (reviewed in Adan et al. 2022).
所含基因
23 个基因