Mechanisms of inhibin signal transduction

Inhibin was first identified as a gonadal hormone that potently inhibits pi tuitary follicle-stimulating hormone (FSH) synthesis and secretion. Althoug h the notion of a nonsteroidal, gonadally derived inhibitory substance was realized in the early 1930s (McCullagh, 1932), identification of the hormon e was not accomplished until more than 50 years later. At that time, inhibi n was purified from bovine and porcine follicular fluid and was shown to be produced in two forms through dimeric assembly of an a subunit (18 kDa) an d one of two closely related beta subunits (PA and PB, approximately 14 kDa ) (Ling er al., 1985; Miyamoto el 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 subu nits (Ling er al., 1986; Vale et al., 1986). These hormones, the activins, were shown to potently stimulate FSH secretion from primary pituitary cultu res and are now known to play important roles in growth and development (Wo odruff, 1998; Pangas and Woodruff, 2000). Inhibins and activins are conside red members of the transforming growth factor-beta (TGF-beta) superfamily o f growth and differentiation factors, based on a pattern of conserved cyste ine residues in the alpha and beta subunits, similar to other ligands in th e family. Identification of the subunit proteins led to the cloning of their cDNAs an d subsequently to their chromosomal mapping in several species (Mason et al ., 1985,1986; Forage et al, 1986; Mayo et at, 1986; Esch el al., 1987; Wood ruff el al., 1987; Barton et al., 1989; Hiendleder et at, 2000). Three addi tional activin-related beta subunits (betaC and betaE in mammals and PD in Xenopus laevis) also have been identified but do not appear to play a role in FSH regulation (Hotten el al., 1995; Oda et al., 1995; Fang et al., 1996 ,1997; Loveland el at, 1996; Schmitt et al., 1996; O'Bryan et at, 2000; Lau et al., 2000). To date, only one a subunit has been reported. The inhibin subunits are expressed in various tissues (Meunier ei at., 1988a,1988b) but the gonads are clearly the primary source of circulating inhibins (Woodruf f el at, 1996). While inhibins act in a paracrine role in some tissues (Hsu eh et al., 1987), their best-understood roles are as endocrine regulators o f pituitary FSH. Activins also were purified from follicular fluid but beca use circulating activin levels generally are low, most actions of the hormo nes are likely to be paracrine in nature (Woodruff, 1998). Several reviews in the past decade have clearly and thoroughly addressed the characterizati on acid regulation of the inhibins and activins and their roles in reproduc tive function (Vale el 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 inhi bin research. First, we discuss differential regulation of inhibin isoforms . Specifically, we describe patterns of inhibin A and B secretion in the co ntext of the female reproductive cycle. Second, we review molecular mechani sms 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 addr essing the possible role of inhibins in gonadal cancers. While we know "wha t" 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 el at, 1999; Lewis et at, 2000; Chung et al., 2000). Next we detail our cu rrent understanding of inhibin signal transduction. Finally, in light of th e data reviewed here, we pose questions and outline future directions for i nhibin research. While this review is concerned primarily with expression a nd function of inhibin, activin function and mechanisms of action are descr ibed 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).