Overview of follicle stimulating hormone and its receptors in reproduction and in stem cells and cancer stem cells

Abstract

Follicle stimulating hormone (FSH) and its receptor (FSHR) have been reported to be responsible for several physiological functions and cancers. The responsiveness of stem cells and cancer stem cells towards the FSH-FSHR system make the function of FSH and its receptors more interesting in the context of cancer biology. This review is comprised of comprehensive information on FSH-FSHR signaling in normal physiology, gonadal stem cells, cancer cells, and potential options of utilizing FSH-FSHR system as an anti-cancer therapeutic target.

Figure 1

Schematic representation of structures of the common subunit (α-) and FSHβ genes (upper panel) and of FSH protein (lower panel). The symbols 'Y' in the lower panel marks the approximate positions of the N-linked carbohydrate side chains in the FSH molecules. Adapted from Huhtaniemi and Aittomaki .

Figure 2

Schematic diagram representing the structural component of FSHR1. FSHR1 structure consist of an N-terminal extracellular domain, transmembrane domains and intracellular domains. Extracellular domain may be further divided into two subdomains, hormone binding domain (HBD) and hinge region. HBD comprises the ten 10 consecutive leucine rich repeats (LRR). Hinge region covers two other LRR, a hair pin loop and an alpha helix. A sulphated tyrosine at the 335^th amino acid position of a hinge loop in the signal-specificity sub-domain is responsible for the hormonal activity. A short intra-cellular domain rich in serine and threonine molecules serve as a potential phosphorylation sites during signal transduction. Leucine rich repeats are demonstrated by the blue colored arrows. The α-Helix in the hinge region is shown as a blue colored cylinder. Transmembrane helices (1-7) are depicted as yellow colored boxes. FSH-α and FSH-β subunits are demonstrated by orange ovoid shapes. ECL: Extracellular loop; ICL: Intracellular loop; ECD: Extracellular domain; TMD: transmembrane domain; HBD: Hormone binding domain. Re-drawn from Figure 2 of Pascali et al. .

Figure 3

Exon structures of FSHR splice variants. Canonical FSHR1 (GPCR) contains 10 exons, with the 7 transmembrane domains encoded by exon number 10. FSHR2 (dominant negative isoform) is the truncated form of FSHR1, where exon 10 is truncated and joined with exon number 11. In FSHR3 (Growth factor type 1 receptor), exons 9 and 10 are spliced out and the transcript is joined to exon 11. FSHR4 is considered to be a soluble-type receptor and only contains exons 1-4. Adapted from Bhartiya and Singh .

Figure 4

Schematic diagram representing the hierarchy of stem cells found in mammalian gonad and their prominent characteristics. VSELs are considered as developmentally equivalent to primordial germ cells due to their spontaneous differentiation into oocytes and sperm like structure during in vitro culture condition. VSELs are quiescent small sized stem cells, exist in gonads and give rise to a marginally bigger SSCs/OSCs that further differentiate into gametes by undergoing symmetrical cell divisions (according to the hypothesis put forward by Bhartiya et. al. (43). Re-drawn from Figure 6.2 of Bhartiya et al. .

Figure 5

Signaling cascades triggered by FSH-FHSR system in target cells. Besides the main Gαs/cAMP/protein kinase A (PKA) pathway that has been believed to be the mainstay of FSH signal transduction within the target cells, accumulating evidences over the last decade show that FSHR can also engage APPL1-mediated signaling, EGFR transactivation and β-arrestin-dependent pathways. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Bloaguen et al. under CC-BY License.

Figure 6

Canonical Gαs/cAMP/PKA pathway at FSHR in target cells. The Gαs/cAMP/PKA pathway has been the most studied and is associated with various intracellular events. It is now acknowledged that PKA is not the sole target of cAMP accumulation. Indeed, EPAC is also activated upon FSH stimulation. Both PKA and EPAC contribute to the activation of MAPK, ERK and p38, whereas EPAC also leads to Akt activation. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Gloaguen et al. under CC-By License.

Figure 7

FSH- induced β-arrestin-dependent pathway. Initially, the perception of β-arrestins' role was restricted to the control of desensitization of FSHR and its recycling. This view has progressively evolved towards a more general role of β-arrestins as adapters and transducers leading to the activation of MAPK, ERK and rpS6 independent of G proteins upon FSH stimulation. GRK2/3 and GRK 5/6 control the fate of the activated FSHR (i.e., desensitization or signaling) presumably through phosphorylation of distinct serine and threonines within the receptor's C-tail. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Gloaguen et al. under CC-BY License.

Figure 8

PI3K/mTOR signaling at FSHR in target cells. The PI3K/mTOR pathway plays an important role in FSH-induced actions, including proliferation, regulation of gene expression as well as protein translation. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Gloaguen et al. Under CC-BY License.

Figure 9

Nuclear events controlled by FSH. Gene transcription has long been known to be affected by FSH. Multiple signaling pathways that are activated upon stimulation (i.e., PKA, p38, ERK and Akt) subsequently trigger the activation or suppression of the activities of various transcription factors within the nucleus. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Gloaguen et. al. under CC-BY License.

Figure 10

Proteins interacting with FSHR thus impacting the signalling pathway. A number of proteins interact with FSHR thus affecting FSH-induced signaling pathways. These include 14-3-3tau, FoxO1 and APPL1, the latter two being involved in the control of the PI3K/Akt pathway downstream of FSHR. Solid lines represent facilitatory outcomes whereas, the dotted ones pertain to the inhibitory results. Adapted from Gloaguen et al. under CC-BY License.