Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor

Inhibition of PRL hormone signaling by suppressor of cytokine signaling (SO CS)/cytokine-inducible SH2-containing protein (CIS) was investigated in tra nsfected HEK 293 cells. We used the physiologically relevant wild-type beta -casein promoter as a target gene for PRL action. We demonstrate that CIS produces a 70% inhibition of PRL signaling by a mechanism distinct from, an d downstream of, the effect of SOCS-1 on JAK2. This inhibition involves ass ociation with the PRL receptor (PRLR), resulting in the inhibition of signa l transducer and activator of transcription 5 (STAT5) activation. Further, we show that SOCS-3 coimmunoprecipitates with the PRLR. These data suggest that SOCS-3 involves a second pathway for the inhibition of PRL signaling o ther than JAK2 inhibition. Additional results indicate that SOCS-2 can play a more important potentiator role on PRL signaling, resulting in a restora tion of 50% of transcriptional inhibition induced by SOCS-3 and a restorati on of 100% of transcriptional inhibition induced by CIS. SOCS-2 was able to block the inhibitory effect of SOCS-1. These results indicate that SOCS-2 seems to be an antagonist of the other SOCS. SOCS-1 binds JAK2 and inhibits its phosphorylation; SOCS-3 does not bind JAK2 but binds the PRLR that may mediate its inhibition of JAK2; and finally, CIS binds the PRLR but inhibi ts signal transducer and activator of transcription 5 rather than JAK2.