School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China.
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16975-80. doi: 10.1073/pnas.1315862110. Epub 2013 Sep 30.
The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.
STAT3 的酪氨酸磷酸化激活对于正常发育和对入侵病原体的正常炎症反应至关重要，但它受到负调控因子的控制。STAT3 的异常持续激活导致癌症和慢性炎症性疾病（如类风湿关节炎）的病理发生，这种异常持续激活发生在负调控不完全有效的情况下。SOCS3 是 STAT3 的主要负调控因子，它被酪氨酸磷酸化的 STAT3 诱导，并在细胞最初暴露于白细胞介素-6 家族细胞因子后的大约 2 小时与共同受体亚基 gp130 和 JAKs1 和 2 协同结合，终止 STAT3 的磷酸化。我们在这里表明，当表皮生长因子受体 (EGFR) 存在并活跃时，细胞暴露于白细胞介素-6 或肿瘤坏死因子-α后大约 4 小时，STAT3 会重新磷酸化，并持续活跃数小时。新合成的白细胞介素-6 驱动白细胞介素-6 受体和 gp130 与 EGFR 结合，导致 EGFR 依赖性 STAT3 重新磷酸化，这不受 SOCS3 持续存在的抑制。这第二波 STAT3 激活支持白细胞介素-6 诱导的蛋白质的一部分的持续表达，其中一些在炎症和癌症中发挥重要作用，在这些疾病中，白细胞介素-6 的分泌和 EGFR 水平通常升高。
