Journal article
PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells
Proceedings of the National Academy of Sciences - PNAS, Vol.109(44), pp.E2979-E2988
PNAS Plus
10/30/2012
Handle:
https://hdl.handle.net/2376/115400
PMCID: PMC3497822
PMID: 23045700
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 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.
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Details
- Title
- PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells
- Creators
- Mary E Hunzicker-Dunn - School of Molecular BiosciencesBlanca Lopez-Biladeau - School of Molecular BiosciencesNathan C Law - School of Molecular BiosciencesSarah E Fiedler - Portland Veterans Affairs Medical CenterDaniel W Carr - Portland Veterans Affairs Medical CenterEvelyn T Maizels - Department of Cell and Molecular Biology
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.109(44), pp.E2979-E2988
- Academic Unit
- Molecular Biosciences, School of
- Series
- PNAS Plus
- Publisher
- National Academy of Sciences
- Identifiers
- 99900548117301842
- Language
- English
- Resource Type
- Journal article