Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling.

Prolactin (PRL) has been shown to activate the cytoplasmic tyrosine kinase Janus kinase 2 (Jak2) and the subsequent recruitment of various signaling molecules including members of the signal transducer and activator of transcription family of transcription factors. Recently, an expanding family of cytokine-inducible inhibitors of signaling has been identified that ...
initially 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. Constitutive expression of SOCS-1 and SOCS-3 suppressed PRL-induced signal transducer and activator of transcription 5-dependent gene transcription, and Jak2 tyrosine kinase activity was greatly reduced in the presence of SOCS-1 or SOCS-3. SOCS-1 was shown to associate with Jak2, whereas SOCS-2 was associated with the prolactin receptor. Co-transfection studies were conducted to further analyze the interactions of SOCS proteins. SOCS-2 was shown to suppress the inhibitory effect of SOCS-1 by restoring Jak2 kinase activity but did not affect the inhibitory effect of SOCS-3 on PRL signaling. Northern blot analysis revealed that SOCS-3 and SOCS-1 genes were transiently expressed 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) switch off PRL signaling and that the later expressed SOCS-2 gene can restore the sensitivity of cells to PRL, partly by suppressing the SOCS-1 inhibitory effect.
Mesh Terms:
Animals, Carrier Proteins, Cell Line, Cytokines, DNA-Binding Proteins, Humans, Immediate-Early Proteins, Intracellular Signaling Peptides and Proteins, Janus Kinase 2, Male, Mice, Mice, Inbred C57BL, Mutation, Phosphorylation, Prolactin, Promoter Regions, Genetic, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, RNA, Messenger, Repressor Proteins, Signal Transduction, Suppression, Genetic, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription Factors, Transcriptional Activation, src Homology Domains
J. Biol. Chem.
Date: Aug. 27, 1999
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