Activins and Inhibins: Roles in Development, Physiology, and Disease
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Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Activins and Inhibins: Roles in Development, Physiology, and Disease Maria Namwanje1 and Chester W. Brown1,2,3 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 2Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 3Texas Children’s Hospital, Houston, Texas 77030 Correspondence: [email protected] Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-b family members activin and inhibin have been shown to participate in a variety of biological processes, from the earliest stages of embryonic devel- opment to highly specialized functions in terminally differentiated cells and tissues. Herein, we present the history, structures, signaling mechanisms, regulation, and biological process- es in which activins and inhibins participate, including several recently discovered biolog- ical activities and functional antagonists. The potential therapeutic relevance of these advances is also discussed. INTRODUCTION, HISTORY AND which the activins and inhibins participate, rep- NOMENCLATURE resenting some of the most fascinating aspects of TGF-b family biology. We will also incorporate he activins and inhibins are among the 33 new biological activities that have been recently Tmembers of the TGF-b family and were first discovered, the potential clinical relevance of described as regulators of follicle-stimulating these advances, and therapeutic challenges. hormone (FSH) secretion and erythropoiesis. The activins and inhibins comprise inte- However, activins and inhibins have since been grally linked components of the TGF-b family. implicated in a variety of biological processes, The activins were originally recognized for ranging from the early stages of embryonic de- their abilities to augment the gonadotropin-re- velopment, to highly specialized functions in leasing hormone (GnRH)-mediated release of terminally differentiated cells and tissues (Yu FSH, and were named “activins” because their et al. 1987; Vassalli et al. 1994; Matzuk et al. effects were functionally opposite to those of 1995c; Aono et al. 1997; Yamaoka et al. 1998; inhibin in this context (Ling et al. 1986a; Vale Molloy et al. 1999; Munz et al. 1999a). Herein, et al. 1986). Activins also augment erythropoi- we provide an overview of the history, protein etin (EPO)-dependent hemoglobin production structures, signaling mechanisms and their reg- in K562 erythroleukemia cells and enhance the ulation, and the many biological processes in proliferation of erythrocyte precursors from Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021881 1 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press M. Namwanje and C.W. Brown human bone marrow cells (Eto et al. 1987; Yu PROCESSING, STRUCTURE AND et al. 1987). SIGNALING Inhibins and activins share common b sub- units, with inhibins occurring as ab hetero- Processing of Ligands dimers, whereas activins are bb homodimers. Because inhibins were discovered and isolated Activins are formed when larger pro-proteins before activins, the b monomers are designated dimerize, followed by cleavage to produce two inhibins bA and bB, and the genes are Inhba mature b monomers, activin A, activin B or and Inhbb, respectively. However, the b mono- activin AB (bA bB) (Ling et al. 1986b; Vale mers are also often referred to as activins bA and et al. 1986). Dimerization of the bAorbB pep- bB, the designations that will be used herein tides with a inhibin (encoded by the Inha gene) (Fig. 1A). Activins bA and bB are closely related followed by cleavage, results in heterodimeric peptides, showing 63% identity and 87% simi- inhibin A and inhibin B, respectively (Fig. 1A) larity within their mature domains. Activins (Antenos et al. 2008). After the pro-proteins are were identified in eluted fractions from porcine synthesized, the prodomains aid in folding and follicular fluid and stimulated FSH secretion in assembling of their mature peptides, by holding vitro from pituitary gonadotropes, which nor- them in a dimerization-competent conforma- mally produce FSH and luteinizing hormone tion (Gray and Mason 1990; Walton et al. 2009, (LH). The eluted proteins were heterodimers 2012). Three amino acids within the inhibin of activin bA and bB monomers (bA bB) a prodomain (Leu30, Phe37, Leu41) form a (Ling et al. 1986b). Homodimers of the bAor hydrophobic interface with the mature peptide, bB monomers (activins A and B, respectively) are required for heterodimer assembly and se- also stimulated FSH release (Ling et al. 1986a; cretion, and are likely to mediate noncovalent Vale et al. 1986; Mason et al. 1989), whereas interactions with the mature domain (Walton inhibin heterodimers (abA and abB, inhibins et al. 2009). A similar relationship exists between A and B, respectively) blocked this effect (Set- the activin bA pro- and mature domains. Mu- chell and Jacks 1974; De Jong and Sharpe 1976). tation of these key amino acids results in greatly Activin C (bC bC) and activin E (bE bE) reduced production of activin A and inhibin A, were later identified with predominant expres- because of the failure of dimerization. Similar sion in liver but also in several other tissues. observations have been made for members of Activin bC and bE monomers also have the other branches of the TGF-b family and suggest capacity to heterodimerize among themselves a possible common paradigm for the pro- (bC bE) with other activin monomers and in- domains in functional assembly of TGF-b fam- hibin a (Fang et al. 1996, 1997; Schmitt et al. ily ligands. Also, mutations in the activin bA 1996; O’Bryan et al. 2000; Hashimoto et al. prodomain greatly reduce its capacity to bind 2002; Vejda et al. 2002; Mellor et al. 2003; the mature domain as well as its ability to inhibit Gold et al. 2004; Ushiro et al. 2006). Activins activin A functions (Walton et al. 2009). C and E are unlikely to signal through activin Differences in posttranslational glycosyla- receptors but rather antagonize activin A signal- tion of the inhibin a subunit substantially affect ing by forming bA bCorbA bE heterodimers, the production, secretion, and bioactivity of as seen in human PC3 prostate tumor cells co- inhibin A and affect its affinity for betaglycan transfected with activins bA and bC (Mellor (Mason et al. 1996; Antenos et al. 2007; Makanji et al. 2003) and in transgenic mice that over- et al. 2007). Failure of normal glycosylation in express activin bC on an inhibin-a-deficient ovarian granulosa cells results in markedly re- genetic background, thereby mitigating the can- duced secretion of inhibin a without impacting cer-cachexia phenotype of Inha2/2 mice (Gold activin assembly and release. Therefore, reduc- et al. 2013). To our knowledge, the ability of tion of inhibin a secretion is predicted to favor activins C or E to inhibit activin B signaling the production of activins more than inhibins, has not been reported. so glycosylation provides a potential mecha- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021881 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Activins and Inhibins A Activin βA pro-protein Mature monomers Mature dimers Prodomain Mature α Activin A (βAβA) 1) Dimerization βB βA Activin βB pro-protein α βB Activin B (βBβB) Prodomain Mature βA 2) Pro-protein cleavage Nascent Activin AB (βAβB) complexes Inhibin α pro-protein Pro-protein β Prodomain Mature convertase A Inhibin A (αβA) βB βA αβ α βB Inhibin B ( B) α Prodomains B Type I activin receptors Type II activin receptors Inhibin receptor Acvr1b (ALK-4) ActRII Betaglycan ActRII ALK-4 ALK-7 Acvr1c (ALK-7) ActRIIb ActRIIB C Activins Inhibins ABBA AB Betaglycan Betaglycan ActRII ActRII ActRIIB ActRII ALK-4 ALK-7 ALK-7 ALK-4 ActRIIB ActRIIB Figure 1. Activin and inhibin ligands and receptors. (A) Activin bA, activin bB, and inhibin a are synthesized as pro-proteins that comprise a prodomain and mature domain. The pro-proteins associate to form homo- or heterodimers, which are ultimately processed into activins A, B, AB, and inhibins A and B. The junctions of the pro- and mature domains are cleaved by pro-protein convertases, resulting in dimer complexes that retain the noncovalently linked prodomains. (B) The two type I receptors for activins are ActRIB (ALK-4) and ActRIC (ALK-7). The two type II receptors are ActRII and ActRIIB. The inhibins antagonize activin signaling by using one type II receptor and one type III TGF-b receptor, betaglycan. (C) The mature activin dimers bind type I and type II receptors to form active signaling complexes. Each activin dimer can bind more than one combination of type I and type II receptors with different affinities, and each type I/type II receptor combination can bind different dimers, including other members of the TGF-b family. The active signaling complex is comprised of one activin dimer, two type I, and two type II receptors. Inhibins competitively antagonize activin signaling by binding one type II receptor and betaglycan, thereby sequestering type II receptors in an inactive complex. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021881 3 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press M. Namwanje and C.W. Brown nism to control the relative levels of activins and their glycine–serine-rich (GS) domains. The inhibins in cells in which they are coexpressed.