PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells

Mary E. Hunzicker-Dunn, Blanca Lopez-Biladeau, Nathan C. Law, Sarah E. Fiedler, Daniel Carr, Evelyn T. Maizels

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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 Thr308 and Ser473. 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 FSHstimulated 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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number44
DOIs
StatePublished - Oct 30 2012

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1-Phosphatidylinositol 4-Kinase
Granulosa Cells
Cyclic AMP-Dependent Protein Kinases
Insulin Receptor Substrate Proteins
Phosphorylation
GRB2 Adaptor Protein
Apoptosis
Proto-Oncogene Proteins c-akt
Ovarian Follicle
Receptor Protein-Tyrosine Kinases
Protein Kinases
Fertility
Catalytic Domain
Carrier Proteins
Steroids
Binding Sites
Hormones
Ligands

ASJC Scopus subject areas

  • General

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PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. / Hunzicker-Dunn, Mary E.; Lopez-Biladeau, Blanca; Law, Nathan C.; Fiedler, Sarah E.; Carr, Daniel; Maizels, Evelyn T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 44, 30.10.2012.

Research output: Contribution to journalArticle

Hunzicker-Dunn, Mary E. ; Lopez-Biladeau, Blanca ; Law, Nathan C. ; Fiedler, Sarah E. ; Carr, Daniel ; Maizels, Evelyn T. / PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 44.
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