Inhibition and restoration of prolactin signal transduction by suppressorsof cytokine signaling

Prolactin (PRL) has been shown to activate the cytoplasmic tyrosine kinase Janus kinase 2 (Jak2) and the subsequent recruitment of various signaling m olecules including members of the signal transducer and activator of transc ription family of transcription factors. Recently, an expanding family of c ytokine-inducible inhibitors of signaling has been identified that initiall y included four members: suppressor of cytokine signaling (SOCS)-1, SOCS-2, SOCS-3, and cytokine-inducible src homology domain 2 (SH-2) proteins. The present study analyzes the role of these members in PRL signaling. Constitu tive expression of SOCS-1 and SOCS-3 suppressed PRL-induced signal transduc er and activator of transcription B-dependent gene transcription, and Jak2 tyrosine kinase activity was greatly reduced in the presence of SOCS-1 or S OCS-3. SOCS-1 was shown to associate with Jak2, whereas SOCS-2 was associat ed with the prolactin receptor. Co-transfection studies were conducted to f urther analyze the interactions of SOCS proteins. SOCS-2 was shown to suppr ess the inhibitory effect of SOCS-1 by restoring Jak2 kinase activity but d id not affect the inhibitory effect of SOCS-3 on PRL signaling. Northern bl ot analysis revealed that SOCS-3 and SOCS-1 genes were transiently expresse d in response to PRL, both in vivo and in vitro, whereas the expression of SOCS-2 and CIS genes was still elevated 24 h after hormonal stimulation. We thus propose that the early expressed SOCS genes (SOCS-1 and SOCS-3) switc h off PRL signaling and that the later expressed SOCS-2 gene can restore th e sensitivity of cells to PRL, partly by suppressing the SOCS-1 inhibitory effect.