Signal transducers and activators of transcription 3 (STAT3) is reported to regulate cell proliferation, survival, and differentiation, and thus plays a central role in development and carcinogenesis. Accumulating evidence demonstrated the involvement of cellular Src (c-Src) tyrosine kinase in the activation of STAT3. Additionally, novel oncogene with kinase-domain (NOK), a receptor protein tyrosine kinase that involves in cell transformation and tumorigenesis, was found to activate STAT3 signaling by a JAK2-dependent mechanism. However, whether the existence of the interaction between c-Src/STAT3 and NOK/STAT3 signals is still unknown. In this study, we showed that NOK formed a complex with c-Src and facilitated the interaction between c-Src and STAT3. In the complex, NOK greatly elevated the c-Src-mediated STAT3 activation by increasing the phosphorylation level of STAT3 on Tyr705. Truncated and mutation experiments further demonstrated that the kinase activity was responsible for the synergistic effect of NOK and c-Src on STAT3 activation. In addition, NOK and c-Src synergistically promoted cell proliferation and tumor growth in nude mice. Taken together, our results indicate that NOK associates with c-Src and promotes c-Src-induced STAT3 activation in a kinase-dependent manner. We proposed that the axis that NOK promoted c-Src-induced STAT3 activation is critical in cell proliferation and tumorigenesis.

据报道，信号转导和转录激活因子 3 (STAT3) 可调节细胞增殖、存活和分化，因此在发育和致癌作用中起着核心作用。越来越多的证据表明细胞 Src (c-Src) 酪氨酸激酶参与了 STAT3 的激活。此外，发现具有激酶结构域 (NOK) 的新型致癌基因（一种参与细胞转化和肿瘤发生的受体蛋白酪氨酸激酶）通过 JAK2 依赖性机制激活 STAT3 信号传导。然而，c-Src/STAT3 和 NOK/STAT3 信号之间是否存在相互作用尚不清楚。在这项研究中，我们发现 NOK 与 c-Src 形成复合物并促进 c-Src 和 STAT3 之间的相互作用。在综合体中，NOK 通过增加 Tyr705 上 STAT3 的磷酸化水平大大提高了 c-Src 介导的 STAT3 激活。截断和突变实验进一步证明激酶活性是 NOK 和 c-Src 对 STAT3 激活的协同作用的原因。此外，NOK 和 c-Src 协同促进裸鼠的细胞增殖和肿瘤生长。总之，我们的结果表明 NOK 与 c-Src 相关并以激酶依赖性方式促进 c-Src 诱导的 STAT3 激活。我们提出 NOK 促进 c-Src 诱导的 STAT3 激活的轴在细胞增殖和肿瘤发生中至关重要。此外，NOK 和 c-Src 协同促进裸鼠的细胞增殖和肿瘤生长。总之，我们的结果表明 NOK 与 c-Src 相关并以激酶依赖性方式促进 c-Src 诱导的 STAT3 激活。我们提出 NOK 促进 c-Src 诱导的 STAT3 激活的轴在细胞增殖和肿瘤发生中至关重要。此外，NOK 和 c-Src 协同促进裸鼠的细胞增殖和肿瘤生长。总之，我们的结果表明 NOK 与 c-Src 相关并以激酶依赖性方式促进 c-Src 诱导的 STAT3 激活。我们提出 NOK 促进 c-Src 诱导的 STAT3 激活的轴在细胞增殖和肿瘤发生中至关重要。