Mechanisms of Hormone Action

Human Follicle-Stimulating Hormone (FSH) Receptor Interacts with the Adaptor Protein APPL1 in HEK 293 Cells: Potential Involvement of the PI3K Pathway in FSH Signaling

Abstract
Selection of a dominant follicle that will ovulate likely occurs by activation of cell survival pathways and suppression of death promoting pathways in a mechanism involving follicle stimulating hormone (FSH) and its cognate receptor (FSHR). A yeast two hybrid screen of an ovarian cDNA library was employed to identify potential interacting partners with human FSHR intracellular loops 1 and 2. Among eight cDNA clones identified in the screen, APPL1 [Adaptor protein containing PH domain, PTB domainand Leucine zipper motif] (also known as APPL or DIP13a) was chosen for further analysis. APPL1 appears to co-immunoprecipitate with FSHR in HEK293 cells stably expressing FSHR, confirming APPL1 as a potential FSHR interacting partner. The phosphorylation status of members of the phosphatidyl inositol-3-kinase (PI3K)/Akt signaling pathway was also examined due to the proposed role of APPL1 in the anti-apoptotic PI3K/Akt pathway. FOXO1a, also referred to as Forkhead Homologue in Rhabdomyosarcoma (FKHR), is a downstream effector in the pathway and tightly linked to expression of pro-apoptotic genes. FOXO1a, but not the upstream kinase Akt, is rapidly phosphorylated and FOXO1a is thereby inactivated when 293/FSHR cells are treated with FSH. In addition, FSHR co-immunoprecipitates with Akt. The identification of APPL1 as a potential interactor with FSHR and the finding that FOXO1a is phosphorylated in response to FSH provide a possible link between FSH and PI3K/Akt signaling, which may help to delineate a survival mechanism whereby FSH selects the dominant follicle to survive.

Key words: Mechanisms of Hormone Action • Apoptosis • Follicle-stimulating hormone • Follicle-stimulating hormone receptor • Signal transduction

This article has been cited by other articles:

				T. Saito, C. C. Jones, S. Huang, M. P. Czech, and P. F. Pilch The Interaction of Akt with APPL1 Is Required for Insulin-stimulated Glut4 Translocation J. Biol. Chem., November 2, 2007; 282(44): 32280 - 32287. [Abstract] [Full Text] [PDF]

				B. D. Looyenga and G. D. Hammer Genetic Removal of Smad3 from Inhibin-Null Mice Attenuates Tumor Progression by Uncoupling Extracellular Mitogenic Signals from the Cell Cycle Machinery Mol. Endocrinol., October 1, 2007; 21(10): 2440 - 2457. [Abstract] [Full Text] [PDF]

				J.-H. Choi, A. S. T. Wong, H.-F. Huang, and P. C. K. Leung Gonadotropins and Ovarian Cancer Endocr. Rev., June 1, 2007; 28(4): 440 - 461. [Abstract] [Full Text] [PDF]

				K. K.Y. Cheng, K. S.L. Lam, Y. Wang, Y. Huang, D. Carling, D. Wu, C. Wong, and A. Xu Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells Diabetes, May 1, 2007; 56(5): 1387 - 1394. [Abstract] [Full Text] [PDF]

				P. C.K. Leung and J.-H. Choi Endocrine signaling in ovarian surface epithelium and cancer Hum. Reprod. Update, March 1, 2007; 13(2): 143 - 162. [Abstract] [Full Text] [PDF]

				S. Ledoux, D. B. Campos, F. L. Lopes, M. Dobias-Goff, M.-F. Palin, and B. D. Murphy Adiponectin Induces Periovulatory Changes in Ovarian Follicular Cells Endocrinology, November 1, 2006; 147(11): 5178 - 5186. [Abstract] [Full Text] [PDF]

				W. Luo and M. C. Wiltbank Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells Biol Reprod, August 1, 2006; 75(2): 217 - 225. [Abstract] [Full Text] [PDF]

				S. Costagliola, E. Urizar, F. Mendive, and G. Vassart Specificity and promiscuity of gonadotropin receptors Reproduction, September 1, 2005; 130(3): 275 - 281. [Abstract] [Full Text] [PDF]

				F. X. Donadeu and M. Ascoli The Differential Effects of the Gonadotropin Receptors on Aromatase Expression in Primary Cultures of Immature Rat Granulosa Cells Are Highly Dependent on the Density of Receptors Expressed and the Activation of the Inositol Phosphate Cascade Endocrinology, September 1, 2005; 146(9): 3907 - 3916. [Abstract] [Full Text] [PDF]

				W. H Walker and J. Cheng FSH and testosterone signaling in Sertoli cells Reproduction, July 1, 2005; 130(1): 15 - 28. [Abstract] [Full Text] [PDF]