NOK associates with c-Src and promotes c-Src-induced STAT3 activation and cell proliferation

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.