Document Detail

PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells.
MedLine Citation:
PMID:  23045700     Owner:  NLM     Status:  MEDLINE    
Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and protein hormones, and induce ligand receptors and signaling intermediates. The phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway is a pivotal signaling corridor necessary for transducing the FSH signal. We report that protein kinase A (PKA) mediates the actions of FSH by signaling through multiple targets to activate PI3K/AKT. PKA uses a route that promotes phosphorylation of insulin receptor substrate-1 (IRS-1) on Tyr(989), a canonical binding site for the 85-kDa regulatory subunit of PI3K that allosterically activates the catalytic subunit. PI3K activation leads to activation of AKT through phosphorylation of AKT on Thr(308) and Ser(473). The adaptor growth factor receptor bound protein 2-associated binding protein 2 (GAB2) is present in a preformed complex with PI3K heterodimer and IRS-1, it is an A-kinase anchoring protein that binds the type I regulatory subunit of PKA, and it is phosphorylated by PKA on Ser(159). Overexpression of GAB2 enhances FSH-stimulated AKT phosphorylation. GAB2, thus, seems to coordinate signals from the FSH-stimulated rise in cAMP that leads to activation of PI3K/AKT. The ability of PKA to commandeer IRS-1 and GAB2, adaptors that normally integrate receptor/nonreceptor tyrosine kinase signaling into PI3K/AKT, reveals a previously unrecognized route for PKA to activate a pathway that promotes proliferation, inhibits apoptosis, enhances translation, and initiates differentiation of granulosa cells.
Mary E Hunzicker-Dunn; Blanca Lopez-Biladeau; Nathan C Law; Sarah E Fiedler; Daniel W Carr; Evelyn T Maizels
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-11-01     Completed Date:  2013-01-08     Revised Date:  2013-07-29    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E2979-88     Citation Subset:  IM    
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
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MeSH Terms
Allosteric Regulation
Catalytic Domain
Cyclic AMP-Dependent Protein Kinases / metabolism*,  physiology
Enzyme Activation
Follicle Stimulating Hormone / metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoproteins / physiology*
Proto-Oncogene Proteins c-akt / metabolism*
Rats, Sprague-Dawley
Signal Transduction / physiology*
Grant Support
Reg. No./Substance:
0/Gab2 protein, rat; 0/Phosphoproteins; 9002-68-0/Follicle Stimulating Hormone; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt; EC AMP-Dependent Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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