Inhibition and Restoration of Prolactin Signal Transduction by Suppressors of Cytokine Signaling*
- From the INSERM U344, Faculté de Médecine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15, France
Abstract
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 andSOCS-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 andSOCS-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.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: INSERM U344, Endocrinologie Moléculaire, Faculté de Médecine Necker Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. Tel.: 33-1-40-61-53-10; Fax: 33-1-43-06-04-43; E-mail: marc.edery@necker.fr.
- Abbreviations:
- PRL
-
prolactin
- PRLR
-
prolactin receptor
- SOCS
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suppressor of cytokine signaling
- CIS
-
cytokine-inducible SH-2 protein
- Jak2
-
Janus kinase 2
- STAT
-
signal transducer and activator of transcription
- LHRE
-
lactogenic hormone-responsive element
- oPRL
-
ovine prolactin
- GH
-
growth hormone
- TK
-
thymidine kinase
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- Received February 8, 1999.
- Revision received May 12, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
