Prolactin Signaling Through the Short Form of Its Receptor Represses Foxo3and Map Kinase Pathways and Activates NFAT Transcription Factor

Y. SANGEETA DEVI, AURORA SHEHU, JULIA HALPERIN, JIFANG MAO AND GEULA GIBORI.

Ventura, USA

Conferencia; 2008 Gordon Research Conference in Prolactin & Growth Hormone Family; 2008

Gordon Research Conferences (GRC)

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman"; mso-ansi-language:ES-AR;} pre {mso-style-noshow:yes; mso-style-unhide:no; mso-style-link:"HTML Preformatted Char"; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Courier New"; mso-fareast-font-family:"Times New Roman";} span.HTMLPreformattedChar {mso-style-name:"HTML Preformatted Char"; mso-style-noshow:yes; mso-style-unhide:no; mso-style-locked:yes; mso-style-link:"HTML Preformatted"; font-family:"Courier New"; mso-ascii-font-family:"Courier New"; mso-fareast-font-family:"Times New Roman"; mso-hansi-font-family:"Courier New"; mso-bidi-font-family:"Courier New";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.0in 1.0in 1.0in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> PRL is critical for the normal function of the ovary in rodents that express both the short (PRL-RS) and long (PRL-RL) form of its cognate receptors. We have recently shown that PRL signaling through PRL-RS in mice expressing only this receptor causes abnormal follicular development and premature ovarian failure suggesting a distinct role of PRL-RS in follicular development and survival. In this investigation we examinedIn the present investigationIn this investigation  the mechanism by which PRL signaling through PRL-RS causes massive follicular death. To this end, we found  that Foxo3, a transcription factor known to regulate follicular development, is profoundly down regulated by PRL signaling through PRL-RS. Using a cell line expressing only PRL-RS, we show that PRL induces Foxo3 protein degradation through a proteasomal-dependent pathway; independent of Jak2 and AKT activation. The degradation of Foxo3 protein in the ovary is accompanied by PRL/PRL-RS mediated activation of calcineurin (a phosphatase that stimulates NFAT transcription factor) as well as inhibition of GSK3 (a kinase which inactivates NFAT). We also found that PRL, signaling through PRL-RS, induces nuclear translocation and stimulates DNA binding activity of NFAT transcription factor. PRL mediated activation of NFAT is not seen in cells expressing PRL-RL indicating that activation of the calcineurin/GSK3/NFAT pathway by PRL is solely through PRL-RS. Of great interest is our finding that the activity of p38 MAP kinase, known to be stimulated under inflammatory cytokines and osmotic shock as a cell survival response, is totally repressed by PRL signaling through PRL-RS. ATF-2 and ELK-1, the downstream targets of p38 MAP kinase, are also severely inhibited by PRL signaling through PRL-RS. However, the upstream kinases MKK3/6 (that phosphorylates and activates p38 MAPK) and MLK3 are not affected by PRL suggesting involvement of phosphatases in the inhibition of p38 MAPK. Surprisingly, there is no change in the expression levels of immediate early genes Map Kinase Phosphatase (MKP)1 and MKP5, known to deactivate p38 MAPK.  However, we observed a marked increase in SHP2 phosphatase activity in response to PRL in cells co-transfected with PRL-RS and JAK2. Taken together, the results of this investigation reveal novel PRL/PRL-RS signaling pathways, which may play important roles in follicular development and survival. Supported by NIH HD12356, HD11119, U54HD40093, HL007692, The American Physiological Society.