Follicle stimulating hormone (FSH) is a glycoprotein hormone secreted by cells called gonadotrophs in the anterior pituitary gland. The major function of FSH is to promote and sustain the ovarian follicular growth in female [1] and spermatogenesis in male [2]. FSH stimulates the synthesis of its own receptor on the granulosa cells of the ovary [3] and in Sertoli cells [4] of the testes. Treatment with FSH also results in the expression of the luteinizing hormone (LH) receptor on granulosa cells [5]. FSH secretion is under the control of pulsatile GnRH release from hypothalamus. The production of estrogen, progesterone and inhibin from ovarian cells is, in turn, controlled by FSH. Estrogen and inhibin regulate FSH secretion through negative feedback on the pituitary [6]. All these dynamic changes in the hypothalamo-pituitary-ovarian axis are required for selection of the dominant follicle, ovulation and thus the menstrual cycle.

FSH is a member of glycoprotein hormone family, which also includes LH, human chorionic gonadotropin (hCG) and the thyroid stimulating hormone (TSH). These hormones are heterodimeric proteins comprised of a common α subunit and a unique β subunit that confers the biological specificity to each hormone. The receptors of these hormones belong to the G-protein coupled receptor (GPCR) superfamily, members of which contain seven transmembrane alpha helical domains [7].

Binding of FSH to its cognate receptor, FSH receptor (FSHR), triggers rapid activation of multiple signaling cascades. FSH action is primarily mediated via activation of the receptor associated heterodimeric G-proteins, which results in stimulation of adenylate cyclase activity and production of cyclic AMP (cAMP) [8]. Consequently, the cAMP-dependent protein kinase (PKA) is activated which in turn leads to phosphorylation of several transcription factors including cAMP responsive element binding protein (CREB), as well as chromatin remodeling through histone H3 modifications [9, 10]. Cyclic AMP/PKA also enhances the activity of p38 mitogen-activated protein kinase (p38MAPK), extracellular signal regulated-kinase (ERK) and phosphatidylinositol-3-kinase (PI3K), which can also be activated by PKA-independent manner [11]. These activated kinases further activate specific transcription factors, which regulate expression of FSH-target genes including aromatase [12], vascular endothelial growth factor VEGF [13], serum- and glucocorticoid-inducible kinase (SGK) [14] and steroidogenic acute regulatory protein (STAR) [15]. Early response genes induced by FSH include cyclin D2, the regulatory subunit of protein kinase A (RII-β) and SGK and the late response genes include cycloxygenase-2 (COX-2) and LH receptor (LHR) [16]. In addition, FSH activates the transcription factor hypoxia-inducible factor-1 (HIF-1) downstream of the PI3-kinase/AKT/Rheb/mTOR axis [17]. Apart from cAMP, FSH increases intracellular concentrations of other second messengers including calcium and inositol 1, 4, 5-triphosphate (IP3) [18, 19].

Although FSH signaling has been relatively well studied, there is a dearth of resources, which provide comprehensive information about the molecules involved in the FSH signaling pathway, the transcription factors activated by FSH and the genes whose expression is eventually regulated. Several online pathway databases including The Database of Cell Signaling (http://stke.sciencemag.org/cm/), KEGG Pathway Database (http://www.genome.jp/kegg/pathway.html), Pathway Interaction Database of the National Cancer Institute (http://pid.nci.nih.gov/) and INOH Pathway Database (http://www.inoh.org/) contain generic information about GPCR signaling. None of these resources provide information specific to FSH-induced signaling. Because of the importance of this pathway in human physiology and disease, we undertook a systematic effort to gather and curate the relevant information available in published literature to create a public resource of the signaling events triggered by FSH.

We have previously developed NetPath [20], a public resource of signaling pathways, with the initial set of annotated pathways focused on those important in immunology and cancer biology. As a next step, we set out to extend this list and generate additional signaling pathways that are relevant to a variety of human physiological processes. Here, we report the development of a pathway map consisting of individual biochemical events that are triggered by the activation of FSH receptor by FSH.

Generation of a curated resource of FSH signaling

The articles relevant to FSH induced signal transduction events were retrieved from PubMed. From these research articles, we documented 11 molecular association events, 35 enzyme-substrate reactions, 11 activation events and 7 protein translocation events that occur upon FSH stimulation. The site of post-translational modifications were also documented and mapped to RefSeq whenever this information was available. FSH pathway reactions are available in NetPath at (http://www.netpath.org/pathways?path_id=NetPath_25) and will be periodically updated. Figure 1 provides an overview of FSH pathway page in NetPath.

Visualization of FSH pathway

There have been efforts by other groups to catalog and represent reactions of signal transduction pathways [21–23]. They have used Systems Biology Graphical Notation (SBGN) for representation of the pathways [24]. Therefore, we used CellDesigner Version 4.1 (http://www.celldesigner.org/) to generate the pathway map in the SBGN format (Figure 2). A high resolution image of the map is provided as Additional File 1. Apart from the protein components involved, small molecules like cAMP, IP3, DAG and Ca⁺⁺ which play a major role in FSH signaling are also represented in the map. Many of the reactions in the current pathway map are derived from a single experiment and may be less reliable. Thus, we have also generated a slim version of the FSH pathway map by applying more stringent criteria (http://www.netpath.org/netslim/fsh_pathway.html). A detailed description of the NetSlim criteria is available at the same portal.

Studies of molecular events that result from activation of various receptors by their ligands are key to understanding various biological processes. Availability of such information serves as an invaluable tool for analyzing various kinds of high-throughput data obtained from gene/protein arrays as well as proteomic experiments. These analyses may include overlaying the high-throughput data onto known pathway reactions as well as perturbation analyses. We here describe the generation of a pathway map of the signaling events that are mediated by activated FSHR, through a systematic and detailed curation of the relevant published literature. This is aimed at providing a global and comprehensive view of the intracellular signaling events as well as the biological processes regulated by FSH. This would also enable researchers to perform various pathway as well as systems biology type of analyses on high-throughput data.