Modulation of activin and BMP signaling (original) (raw)
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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
Cellular Signalling, 2013
TGFβ superfamily ligands greatly outnumber their receptors. Thus, receptors are shared between ligands and individual ligands can bind multiple receptors. Bone morphogenetic proteins (BMPs) bind and signal via both BMP type II (BMPR2) and activin type II (ACVR2) receptors. We hypothesized that, in addition to its canonical receptor ACVR2, activin A might similarly bind and signal via BMPR2. First, using surface plasmon resonance, we showed that activin A binds to the BMPR2 extracellular domain (ECD), though with lower affinity compared to the ACVR2-ECD. We confirmed these results in cells, where radiolabeled activin A bound to ACVR2 and BMPR2, but not to other type II receptors (AMHR2 or TGFBR2). Using homology modeling and site-directed mutagenesis, we identified key residues in BMPR2 that mediate its interaction with activin A. The soluble ECDs of ACVR2 or BMPR2 dose-dependently inhibited activin A-, but not TGFβ-induced signaling in cells, suggesting that activin binding to BMPR2 could have functional consequences. To address this idea, we altered BMPR2 expression levels in immortalized murine gonadotrope-like cells, LβT2, in which activins potently stimulate follicle-stimulating hormone β (Fshb) subunit transcription. BMPR2 expression potentiated activin A responses whereas depletion of endogenous BMPR2 with short interfering RNAs attenuated activin A-stimulated Fshb transcription. Additional data suggest, for the first time, that BMPR2 may form functional complexes with the canonical activin type I receptor, activin receptor-like kinase 4. Collectively, our data show that BMPR2, along with ACVR2, functions as a bona fide activin type II receptor in gonadotrope-like cells, thereby broadening our understanding of mechanisms of activin action.
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.
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.
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).
BMC Biology, 2022
Background Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal to distinct Smad branches; activins signal mainly to Smad2/3, while BMPs activate mainly Smad1/5/8. This gives rise to the possibility that competition between the different type I receptors through which activin and BMP signal for common type II receptors can provide a mechanism for fine-tuning the cellular response to activin/BMP stimuli. Among the transforming growth factor-β superfamily type II receptors, ACVR2A/B are highly promiscuous, due to their ability to interact with different type I receptors (e.g., ALK4 vs. ALK2/3/6) and with their respective ligands [activin A (ActA) vs. BMP9/2]. However, studies on complex formation between these full-length receptors situated at the plasma membrane, and especially on the potential competition between the different activin and BMP type I receptors for a comm...
Scientific Reports, 2019
Bone morphogenetic proteins (BMPs) are multifunctional cytokines of the transforming growth factor β (TGFβ) superfamily with potential therapeutic applications due to their broad biological functionality. Designing BMP mimetics with specific activity will contribute to the translational potential of BMP-based therapies. Here, we report a BMP9 peptide mimetic, P3, designed from the type I receptor binding site, which showed millimolar binding affinities for the type I receptor activin receptor like kinase 1 (ALK1), ALK2 and ALK3. Although showing no baseline activity, P3 significantly enhanced BMP9-induced Smad1/5 phosphorylation as well as ID1, BMPR2, HEY1 and HEY2 gene expression in pulmonary artery endothelial cells (hPAECs), and this activity is dependent on its alpha helix propensity. However, in human dermal microvascular endothelial cells, P3 did not affect BMP9-induced Smad1/5 phosphorylation, but potently inhibited ALK3-dependent BMP4-induced Smad1/5 phosphorylation and gene...
Signal Transduction: Gain of Activin Turns Muscle into Bone
Current Biology, 2015
Recent data provide an unexpected twist in our understanding of the pathogenesis of fibrodysplasia ossificans progressiva. Surprisingly, the causative amino acid mutation of the BMP receptor responds to activin, thereby turning soft tissues into bone.