Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways (original) (raw)
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Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B
Cell Communication and Signaling, 2015
Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6.
Activin A, a ligand that belongs to the BMP/TGFβ family, functions in BMP signaling in two distinctly different ways: it binds to its cognate type II receptors — ACVR2A, ACVR2B, and BMPR2 — and the resulting complex either engages the type I receptor ACVR1B to activate Smad2/3 signaling or binds with the type I receptor ACVR1 to form a non-signaling complex. In order to set the stage for exploring potential biological roles of the non-signaling complex, we engineered Activin A variants that retain their ability to activate ACVR1B but are unable to generate the Activin A · type II receptor · ACVR1 non-signaling complex. This was accomplished by designing Activin A muteins wherein type I-binding regions were replaced with those of Nodal, a BMP/TGFβ family member that utilizes ACVR1B but not ACVR1 as its type I receptor. Of the resulting muteins, an Activin A utilizing the finger 2 tip loop of Nodal (Activin A.Nod.F2TL) fulfilled our specifications; it failed to generate the non-signal...
Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects
The Journal of Cell Biology, 1995
Proteins in the TGF-[~ superfamily transduce their effects through binding to type I and type II serine/threonine kinase receptors. Osteogenic protein-1 (OP-1, also known as bone morphogenetic protein-7 or BMP-7), a member of the TGF-[3 superfamily which belongs to the BMP subfamily, was found to bind activin receptor type I (ActR-I), and BMP receptors type IA (BMPR-IA) and type IB (BMPR-IB) in the presence of activin receptors type II (ActR-II) and type liB (ActR-IIB). The binding affinity of OP-1 to ActR-II was two-to threefold lower than that of activin A. A transcriptional activation signal was transduced after binding of OP-1 to the complex of ActR-I and ActR-II, or that of BMPR-IB and ActR-II. These results indicate that ActR-II can act as a functional type II recep-tor for OP-1, as well as for activins. Some of the known biological effects of activin were observed for OP-1, including growth inhibition and erythroid differentiation induction. Compared to activin, OP-1 was shown to be
Development
During early embryogenesis of Xenopus, dorsoventral polarity of the mesoderm is established by dorsalizing and ventralizing agents, which are presumably mediated by the activity of an activin/BVg1-like protein and Bone Morphogenetic Proteins (BMP), respectively. Interestingly, these two TGF-beta subfamilies are found in overlapping regions during mesoderm patterning. This raises the question of how the presumptive mesodermal cells recognize the multiple TGF-beta signals and differentially interpret this information to assign a particular cell fate. In this study, we have exploited the well characterized model of Xenopus mesoderm induction to determine the intracellular interactions between BMP-2/4 and activin/BVg1 signaling cascades. Using a constitutively active BMP-2/4 receptor that transduces BMP-2/4 signals in a ligand-independent fashion, we demonstrate that signals provided by activin/BVg1 and BMP modulate each other's activity and that this crosstalk occurs through intrac...
A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity
Proceedings of The National Academy of Sciences, 2008
Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF- superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF- signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility.
Journal of Biological Chemistry, 2010
The single transmembrane domain serine/threonine kinase activin receptor type IIB (ActRIIB) has been proposed to bind key regulators of skeletal muscle mass development, including the ligands GDF-8 (myostatin) and GDF-11 (BMP-11). Here we provide a detailed kinetic characterization of ActRIIB binding to several low and high affinity ligands using a soluble activin receptor type IIB-Fc chimera (ActRIIB.Fc). We show that both GDF-8 and GDF-11 bind the extracellular domain of ActRIIB with affinities comparable with those of activin A, a known high affinity ActRIIB ligand, whereas BMP-2 and BMP-7 affinities for ActRIIB are at least 100-fold lower. Using site-directed mutagenesis, we demonstrate that ActRIIB binds GDF-11 and activin A in different ways such as, for example, substitutions in ActRIIB Leu 79 effectively abolish ActRIIB binding to activin A yet not to GDF-11. Native ActRIIB has four isoforms that differ in the length of the C-terminal portion of their extracellular domains. We demonstrate that the C terminus of the ActRIIB extracellular domain is crucial for maintaining biological activity of the ActRIIB.Fc receptor chimera. In addition, we show that glycosylation of ActRIIB is not required for binding to activin A or GDF-11. Together, our findings reveal binding specificity and activity determinants of the ActRIIB receptor that combine to effect specificity in the activation of distinct signaling pathways. The cytokine transforming growth factor  (TGF-) 2 and its homologs, including bone morphogenic proteins (BMPs), activins, and growth and differentiation factors (GDFs), comprise a large superfamily that controls many major cellular processes, including proliferation, differentiation, apoptosis, angiogenesis, and steroid synthesis (1-4). TGF- superfamily members (ligands) form covalently and non-covalently linked homo-and heterodimers that bind two type I and two type II serine/threonine kinase receptors at the same time. Both receptor types consist of an extracellular ligand-binding domain, a single transmembrane span, and a cytoplasmic serine/threonine kinase domain. Formation of the hexameric receptor-ligand complex causes the constitutively active type II receptor kinase to phosphorylate type I receptor. Thus, activated type I receptors phosphorylate Smad proteins, which subsequently translocate into the nucleus and control expression of different genes (2, 5, 6). Five type II receptors have been identified: ActRIIA, ActRIIB, BMPRII, TGFRII, and MISRII. The ActRIIB receptor is of particular interest because it binds multiple ligands from the activin, GDF, and BMP subgroups. ActRIIB extracellular domain (ECD) sequence is exceptionally conserved, with only one amino acid difference between mice and humans and ϳ90% identity between species as divergent as chickens and humans. Although ActRIIB-deficient mice develop to term, most animals (ϳ70%) die shortly after birth (4). Disruption of ActRIIB expression leads to cardiac and kidney malformation, defects in axial patterning, and disturbance of left-right asymmetry in mice (7). Four different isoforms of ActRIIB were found in mice and humans (ActRIIB 1 , ActRIIB 2 , ActRIIB 3 , and ActRIIB 4). The ECDs of ActRIIB 1 and ActRIIB 2 contain an insertion in the C-terminal portion of the ECD that is absent in isoforms ActRIIB 3 and ActRIIB 4. The biological significance of the different isoforms remains unclear. The ActRIIB 2 isoform is most predominant in humans. It was previously suggested that the longer isoforms are the most potent. For example, the longer isoforms ActRIIB 1 and ActRIIB 2 have been shown to have a 3-4-fold higher affinity for activin A than the shorter isoforms ActRIIB 3 and ActRIIB 4 (8). ActRIIB binds to a diverse group of TGF- family members, including activin A, BMP-2, BMP-7, GDF-8 (growth and differentiation factor 8 or myostatin), and GDF-11. Activin A, one of the most abundant proteins of the TGF-/BMP family, is thought to be a negative regulator of bone formation and other tissues (9); BMP-2 has been associated with ectopic bone formation and periarticular ossification (10); BMP-7 has been associated with bone homeostasis (11) and kidney development (12); and GDF-8 and GDF-11 are associated with negative regulation of skeletal muscle mass (13). Moreover, activins and BMPs are known also to use different signaling pathways. Thus, recruitment of BMPs or activins leads to activation of different Smad signaling events. For example, activin binding to ActRIIB leads to activation of the Smad2/3 pathway, whereas binding to BMP-2 results in activation of the Smad1/5/8 pathway (14).
Modulation of activin and BMP signaling
Molecular and Cellular Endocrinology, 2004
Activins and bone morphogenetic proteins (BMPs) elicit diverse biological responses by signaling through two pairs of structurally related types I and II receptors. Here, we summarize recent advances in understanding the mode of action of activins and BMPs, focusing on our elucidation of the crystal structure of BMP-7 in complex with the extracellular domain (ECD) of the activin type II receptor and our identification of a binding site for activin on the type I receptor ALK4. As a consequence of the broad range of activities of activins and BMPs, it is perhaps not surprising that additional mechanisms are continually being discovered through which a cell's responsiveness to these ligands is modulated. In this review, we describe novel ways in which the two extracellular cofactors, betaglycan and Cripto, regulate BMP and/or activin signal transduction.
Roles of Pathway-Specific and Inhibitory Smads in Activin Receptor Signaling
Molecular Endocrinology, 1999
Activins and other members of the transforming growth factor--like superfamily of growth factors transduce their signals by interacting with two types of receptor serine/threonine kinases. The Smad proteins, a new family of intracellular mediators are involved in the signaling pathways of these receptors, but the initial stages of their activation as well as their specific functions remain to be defined. We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a liganddependent manner. This complex formation is rapid but also transient. Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. Finally, we show that the inhibitory Smad7 can prevent the association of the two pathway-specific Smads with the activin receptor complex, thereby blocking the activin signal. (Molecular Endocrinology 13: 15-23, 1999)
Journal of Biological Chemistry, 1997
Members of the transforming growth factor-beta (TGF-beta) superfamily signal via different heteromeric complexes of two sequentially acting serine/threonine kinase receptors, i.e. type I and type II receptors. We generated two different chimeric TGF-beta superfamily receptors, i.e. TbetaR-I/BMPR-IB, containing the extracellular domain of TGF-beta type I receptor (TbetaR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TbetaR-II/ActR-IIB, containing the extracellular domain of TGF-beta type II receptor (TbetaR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB). In the presence of TGF-beta1, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed heteromeric complexes with wild-type TbetaR-II and TbetaR-I, respectively, upon stable transfection in mink lung epithelial cell lines. We show that TbetaR-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TbetaR-II with respect to TGF-beta-mediated activation of a transcriptional signal, extracellular matrix formation, growth inhibition, and Smad phosphorylation. Moreover, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed a functional complex in response to TGF-beta and induced phosphorylation of Smad1. However, complex formation is not enough for signal propagation, which is shown by the inability of TbetaR-I/BMPR-IB to restore responsiveness to TGF-beta in cell lines deficient in functional TbetaR-I. The fact that the TGF-beta1-induced complex between TbetaR-II/ActR-IIB and TbetaR-I stimulated endogenous Smad2 phosphorylation, a TGF-beta-like response, is in agreement with the current model for receptor activation in which the type I receptor determines signal specificity.