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AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells

  • Reproductive Biology: Original Article
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Abstract

Granulosa cells (GCs) must respond appropriately to follicle-stimulating hormone (FSH) for proper follicle maturation. FSH activates protein kinase A (PKA) leading to phosphorylation of the cyclic AMP response element binding protein-1 (CREB1). We identified a unique A-kinase anchoring protein (AKAP13) containing a Rho guanine nucleotide exchange factor (RhoGEF) region that was induced in GCs during folliculogenesis. AKAPs are known to coordinate signaling cascades, and we sought to evaluate the role of AKAP13 in GCs in response to FSH. Aromatase reporter activity was increased in COV434 human GCs overexpressing AKAP13. Addition of FSH, or the PKA activator forskolin, significantly enhanced this activity by 1.5- to 2.5-fold, respectively (p < 0.001). Treatment with the PKA inhibitor H89 significantly reduced AKAP13-dependent activation of an aromatase reporter (p = 0.0067). AKAP13 physically interacted with CREB1 in co-immunoprecipitation experiments and increased the phosphorylation of CREB1. CREB1 phosphorylation increased after FSH treatment in a time-specific manner, and this effect was reduced by siRNA directed against AKAP13 (p = 0.05). CREB1 activation increased by 18.5-fold with co-expression of AKAP13 in the presence of FSH (p < 0.001). Aromatase reporter activity was reduced by inhibitors of the RhoGEF region, C3 transferase and A13, and greatly enhanced by the RhoGEF activator, A02. In primary murine and COV43 GCs, siRNA knockdown of Akap13/AKAP13 decreased aromatase and luteinizing hormone receptor transcripts in cells treated with FSH, compared with controls. Collectively, these findings suggest that AKAP13 may function as a scaffolding protein in FSH signal transduction via an interaction with CREB, resulting in phosphorylation of CREB.

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Acknowledgements

The authors thank Joshua T. Brennan, M.S., MPH and Md Soriful Islam, Ph.D.

Funding

Research reported in this publication was supported in part by the Howard and Georgeanna Jones Endowment; National Institutes of Health Grant ZIA-HD-008737–11 (to J.H.S.); the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number K12-HD-103036 (to K.C.V); the Society for Reproductive Investigation and Bayer Discovery Innovation Grant (to K.C.V); the Clinical Research Training Program, a public–private partnership supported jointly by the National Institutes of Health (to K.D. and M.M.); the Johns Hopkins University School of Medicine Predoctoral Research Program for Medical Students (Dean’s Year of Research) (to A.S.C.); NIH ZIA-HD-008985 (to J.Y.M.); and the Edward E. Wallach Research Award (to J.Y.M.).

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Authors and Affiliations

  1. Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Kamaria C. Cayton Vaught, Ashlie Sewdass Carter, Jacqueline Y. Maher, Paul H. Driggers & James H. Segars

  2. American University of Beirut Medical Centre, Beirut, Lebanon

    Dana Hazimeh

  3. Section On Reproductive Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Kate Devine & Marcy Maguire

  4. Shady Grove Fertility, Washington, DC, 20006, USA

    Kate Devine

  5. Section On Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Jacqueline Y. Maher

  6. Reproductive Medicine Associates of New Jersey, West Orange, NJ, 07052, USA

    Marcy Maguire

  7. Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Vermont, Burlington, VT, 05405, USA

    Elizabeth A. McGee

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  1. Kamaria C. Cayton Vaught
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Kamaria C. Cayton Vaught, Kate Devine, Ashlie Sewdass, Jacqueline Y. Maher, Dana Hazimeh, Marcy Maguire, Elizabeth A. McGee, Paul H. Driggers, and James H. Segars. The first draft of the manuscript was written by Kamaria C. Cayton Vaught and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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All experimental procedures involving animals were conducted in accordance with the Intuitional Animal Care and Use Committees at the National Institute of Health. Animals were cared for as per institutional regulations under the reviewed and approved animal study protocols, ASP 03–001, ASP 06–002, ASP 12–060, and ASP 15–060.

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Cayton Vaught, K.C., Hazimeh, D., Carter, A.S. et al. AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells. Reprod. Sci. 30, 1528–1539 (2023). https://doi.org/10.1007/s43032-022-01097-5

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