SOCS-1, -2, -3: selective targets and functions downstream of the prolactin receptor

Suppressors of cytokine signaling, SOCS-1, SOCS-2 and SOCS-3, are non-transmembrane proteins with Src-homology-2 (SH2) domain, involved in negative regulation of the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway. Using transient overexpression system the role of SOCS proteins in regulating prolactin receptor intracellular mediators leading to gene activation was analyzed. Overexpression of SOCS-1 led to a significant reduction in PRLR-mediated tyrosyl phosphorylation of Jak2, PRLR, Stat5 and the cytoplasmic protein tyrosine phosphatase SHP2. Overexpression of SOCS-3 however, led to selective inhibition in PRLR-mediated tyrosyl phosphorylation of Jak2, the PRLR as well as SHP2. On the other hand, overexpression of SOCS-2 had no inhibitory effects on the tyrosyl phosphorylation status of the PRLR, Jak2, Stat5 or SHP2 in response to PRLR activation. Finally, the role of SOCS proteins in regulating the biological activity of the PRLR was investigated. Unlike SOCS-2, both SOCS-1 and SOCS-3 abolished the ability of the PRLR to induce beta-casein gene promoter activation. These results demonstrate that SOCS-1, SOCS-2 and SOCS-3 are differentially implicated in PRLR signaling to gene activation.