Molecular interactions between STAT3 and protein inhibitor of activated STAT3, and androgen receptor.

STAT3 mainly acts as a signal transducer of IL-6 family cytokines and transcriptionally activates specific target genes. The recently discovered protein inhibitor of activated STAT3 (PIAS3) binds directly to STAT3 and blocks transcriptional activation. In our previous report, we demonstrated that PIAS3 directly interacted with androgen receptor (AR) and affected AR-mediated gene activation. Furthermore, we also showed that AR associated with STAT3 and enhanced its activity. Here, we examined molecular interactions between STAT3, PIAS3, and AR to underline the mechanism of how they regulate each other. AR activation overcame the inhibitory effect on STAT3-mediated transcription by PIAS3. Co-immunoprecipitation experiments revealed that an active form of AR relieved STAT3 from STAT3-PIAS3 complex formation. These results indicate that AR and PIAS3 regulate the STAT3-mediated transcriptional activity by their physical protein-protein competition on STAT3.