scholarly journals Convergence of 3′,5′-Cyclic Adenosine 5′-Monophosphate/Protein Kinase A and Glycogen Synthase Kinase-3β/β-Catenin Signaling in Corpus Luteum Progesterone Synthesis

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5036-5045 ◽  
Author(s):  
Lynn Roy ◽  
Claudia A. McDonald ◽  
Chao Jiang ◽  
Dulce Maroni ◽  
Anthony J. Zeleznik ◽  
...  

Progesterone secretion by the steroidogenic cells of the corpus luteum (CL) is essential for reproduction. Progesterone synthesis is under the control of LH, but the exact mechanism of this regulation is unknown. It is established that LH stimulates the LH receptor/choriogonadotropin receptor, a G-protein coupled receptor, to increase cAMP and activate cAMP-dependent protein kinase A (PKA). In the present study, we tested the hypothesis that cAMP/PKA-dependent regulation of the Wnt pathway components glycogen synthase kinase (GSK)-3β and β-catenin contributes to LH-dependent steroidogenesis in luteal cells. We observed that LH via a cAMP/PKA-dependent mechanism stimulated the phosphorylation of GSK3β at N-terminal Ser9 causing its inactivation and resulted in the accumulation of β-catenin. Overexpression of N-terminal truncated β-catenin (Δ90 β-catenin), which lacks the phosphorylation sites responsible for its destruction, significantly augmented LH-stimulated progesterone secretion. In contrast, overexpression of a constitutively active mutant of GSK3β (GSK-S9A) reduced β-catenin levels and inhibited LH-stimulated steroidogenesis. Chromatin immunoprecipitation assays demonstrated the association of β-catenin with the proximal promoter of the StAR gene, a gene that expresses the steroidogenic acute regulatory protein, which is a cholesterol transport protein that controls a rate-limiting step in steroidogenesis. Collectively these data suggest that cAMP/PKA regulation of GSK3β/β-catenin signaling may contribute to the acute increase in progesterone production in response to LH.

2000 ◽  
Vol 97 (22) ◽  
pp. 11960-11965 ◽  
Author(s):  
X. Fang ◽  
S. X. Yu ◽  
Y. Lu ◽  
R. C. Bast ◽  
J. R. Woodgett ◽  
...  

2015 ◽  
Vol 290 (32) ◽  
pp. 19445-19457 ◽  
Author(s):  
Jennifer L. Whiting ◽  
Patrick J. Nygren ◽  
Brian J. Tunquist ◽  
Lorene K. Langeberg ◽  
Ole-Morten Seternes ◽  
...  

2006 ◽  
Vol 26 (11) ◽  
pp. 4316-4326 ◽  
Author(s):  
Denis Tempé ◽  
Mariana Casas ◽  
Sonia Karaz ◽  
Marie-Françoise Blanchet-Tournier ◽  
Jean-Paul Concordet

ABSTRACT Gli3 is a zinc finger transcription factor proteolytically processed into a truncated repressor lacking C-terminal activation domains. Gli3 processing is stimulated by protein kinase A (PKA) and inhibited by Hedgehog signaling, a major signaling pathway in vertebrate development and disease. We show here that multisite glycogen synthase kinase 3β (GSK3β) phosphorylation and ubiquitination by SCFβTrCP are required for Gli3 processing. We identified multiple βTrCP-binding sites related to the DSGX2 - 4S motif in Gli3, which are intertwined with PKA and GSK3β sites, and SCFβTrCP target lysines that are essential for processing. Our results support a simple model whereby PKA triggers a cascade of Gli3 phosphorylation by GSK3β and CK1 that leads to direct βTrCP binding and ubiquitination by SCFβTrCP. Binding of βTrCP to Gli3 N- and C-terminal domains lacking DSGX2 - 4S-related motifs was also observed, which could reflect indirect interaction via other components of Hedgehog signaling, such as the tumor suppressor Sufu. Gli3 therefore joins a small set of transcription factors whose processing is regulated by the ubiquitin-proteasome pathway. Our study sheds light on the role of PKA phosphorylation in Gli3 processing and will help to analyze how dose-dependent tuning of Gli3 processing is achieved by Hedgehog signaling.


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