Mechanisms of inhibin signal transduction

Inhibin was first identified as a gonadal hormone that potently inhibits pituitary follicle-stimulating hormone (FSH) synthesis and secretion. Although the notion of a nonsteroidal, gonadally derived inhibitory substance was realized in the early 1930s (McCullagh, 1932), identification of the hormone was not accomplished until more than 50 years later. At that time, inhibin was purified from bovine and porcine follicular fluid and was shown to be produced in two forms through dimeric assembly of an alpha subunit (18 kDa) and one of two closely related beta subunits (betaA and betaB, approximately 14 kDa) (Ling et al., 1985; Miyamoto et al., 1985; Rivier et al., 1985; Robertson et al., 1985). Dimers of alpha and betaA and alpha and betaB subunits form inhibin A and inhibin B, respectively. In the process of purifying inhibin, two groups also identified homo- and heterodimers of the inhibin beta subunits (Ling et al., 1986; Vale et al., 1986). These hormones, the activins, were shown to potently stimulate FSH secretion from primary pituitary cultures and are now known to play important roles in growth and development (Woodruff, 1998; Pangas and Woodruff, 2000). Inhibins and activins are considered members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors, based on a pattern of conserved cysteine residues in the alpha and beta subunits, similar to other ligands in the family. Identification of the subunit proteins led to the cloning of their cDNAs and subsequently to their chromosomal mapping in several species (Mason et al, 1985,1986; Forage et al., 1986; Mayo et al., 1986; Esch et al., 1987; Woodruff et al., 1987; Barton et al., 1989; Hiendleder et al., 2000). Three additional activin-related beta subunits (betaC and betaE in mammals and betaD in Xenopus laevis) also have been identified but do not appear to play a role in FSH regulation (Hotten et al., 1995; Oda et al., 1995; Fang et al., 1996, 1997; Loveland et al., 1996; Schmitt el al., 1996; O'Bryan et al., 2000; Lau et al., 2000). To date, only one alpha subunit has been reported. The inhibin subunits are expressed in various tissues (Meunier et al., 1988a, 1988b) but the gonads are clearly the primary source of circulating inhibins (Woodruff et al., 1996). While inhibins act in a paracrine role in some tissues (Hsueh et al., 1987), their best-understood roles are as endocrine regulators of pituitary FSH. Activins also were purified from follicular fluid but because circulating activin levels generally are low, most actions of the hormones are likely to be paracrine in nature (Woodruff, 1998). Several reviews in the past decade have clearly and thoroughly addressed the characterization and regulation of the inhibins and activins and their roles in reproductive function (Vale et al., 1988; Ying, 1988; Woodruff and Mayo, 1990; Mayo, 1994; Woodruff and Mather, 1995). In this chapter, we focus our attention on more-recent developments in inhibin research. First, we discuss differential regulation of inhibin isoforms. Specifically, we describe patterns of inhibin A and B secretion in the context of the female reproductive cycle. Second, we review molecular mechanisms of inhibin subunit regulation. Third, while inhibins are best known for their role in pituitary FSH regulation, other functions of the ligands are becoming better understood. We review the animal and human literature addressing the possible role of inhibins in gonadal cancers. While we know "what" inhibins do in various contexts, we have a very limited understanding of "how" the ligands have their effects on target cells. Recently, candidate inhibin receptor molecules have been identified (Draper et al., 1998; Hertan et al., 1999; Lewis et al., 2000; Chung et al., 2000). Next, we detail our current understanding of inhibin signal transduction. Finally, in light of the data reviewed here, we pose questions and outline future directions for inhibin research. While this review is concerned primarily with expression and function of inhibin, activin function and mechanisms of action are described where necessary to shed light on inhibin function. Several reviews of activin's role in reproductive and other processes can be found elsewhere (Woodruff, 1998; Pangas and Woodruff, 2000).