The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Aykul, Senem; Ra, Corpina; Ej, Goebel; Cj, Cunanan; Dimitriou, Alexandra; Kim, Ho; Zhang, Q; Rafique, Ashique; Leidich, Raymond; Wang, X; McClain, Joyce; Jimenez, Johanna; Kc, Nannuru; Nj, Rothman; Jb, Lees-Shepard; Martı́nez-Hackert, Erik; Murphy, Andrew J.; Tb, Thompson; An, Economides; Idone, Vincent

doi:10.1101/733147

Cited by 3 publications

(7 citation statements)

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“…Sequences both in the receptors and the ligand determine binding specificity and strength. Recent studies have suggested that the finger 2 tip loops in activin A and GDF11 are important for their type I receptor binding specificities [44,45]. Moreover, in some cell types, only mutated ALK2, such as the variant encoded by ACVR1 (R206H), has been shown to relay a signal to SMAD1/5 after activin binding [11,12].…”

Section: Discussionmentioning

confidence: 99%

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

et al. 2020

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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.

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Section: Discussionmentioning

confidence: 99%

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

et al. 2020

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“…This lack of responsiveness was not due to competition between activin A and BMPs for binding to ACVR1-containing receptor complexes (see refs. (7,10,11)), as globally recombined R26 ACVR1/+ mice were refractile to injury-induced HO even under conditions of antibody-mediated inhibition of activin A (unpublished observations). These data could indicate that BMPs that signal through ACVR1, such as BMP5, BMP6 and BMP7 (37,55,56), are not available at sufficient levels in skeletal muscles and associated connective tissues to elicit an osteogenic response from presumptively hyper-responsive cells.…”

Section: Discussionmentioning

confidence: 85%

“…Examples include sensitizing cells to BMP ligands that signal through ACVR1 (37,51), reducing SMAD2/3 signaling by sequestration of activins into inactive complexes (7,11), or dampening signaling by other TGFβ family ligands and type I receptors by reducing availability of shared . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas BMP6 can signal through ACVR1 and activate osteogenic signaling of both wild-type and FOP cells, most studies have shown that osteogenic signaling in response to activin A is dependent on ACVR1(R206H) (7)(8)(9)(10)(11). Fluorescence-activated cell sorting was used to isolate FAPs from total hindlimb muscles of control mice (R26 NG/+ ), ACVR1 over-expressing mice (R26 ACVR1/NG ), and FOP mice that either carried (Acvr1 tnR206H/+ ;R26 ACVR1/NG ;Tie2-Cre) or lacked (Acvr1 tnR206H/+ ;R26 NG/+ ;Tie2-Cre) the germline transmitted R26 ACVR1 allele, as previously described (9,21,27).…”

Section: Effects Of Acvr1 Over-expression On Activin A-induced Osteogenic Signalingmentioning

confidence: 99%

“…The great majority of FOP cases are caused by a single arginine to histidine amino acid substitution (R206H) in the intracellular glycine/serine-rich domain of the type 1 bone morphogenetic protein (BMP) receptor ACVR1 (3,4). This amino acid substitution not only renders cells mildly hypersensitive to BMP ligands (5,6) but also alters signaling specificity such that SMAD 1/5/8 phosphorylation and osteogenic differentiation is elicited by activin ligands (7)(8)(9), which normally activate SMAD 2/3 and function as inhibitors of BMP signaling (7,10,11). In fact, recent data has shown that activin A is both necessary and sufficient for HO flares, and its inhibition suppresses growth of nascent lesions in mouse models of FOP (7,9,12,13).…”

Section: Introductionmentioning

confidence: 99%

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Over-expression of wild-typeACVR1in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification

Yamamoto

Stoessel

Yamamoto

et al. 2021

Preprint

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Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally over-express human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 over-expression and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive over-expression of ACVR1 also provided protection from spontaneous HO, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 over-expression functions cell-autonomously by reducing osteogenic signaling in response to activin A. Manipulating the stoichiometry of FOP-causing and wild-type ACVR1 receptors may provide the foundation for novel therapeutic strategies to treat this devastating disease.

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Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development

MacDonnell

Megna

Ruan

et al. 2022

Front. Cardiovasc. Med.

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Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1β induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes (SERCA2, RYR2, CACNB2). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure.

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The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Cited by 3 publications

References 49 publications

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

Over-expression of wild-typeACVR1in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification

Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development

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