Antagonism of Activin by Activin Chimeras

Muenster, Uwe; Korupolu, Radhika; Rastogi, R N; Read, Jessica; Fischer, Wolfgang

doi:10.1016/b978-0-12-385961-7.00006-8

Cited by 5 publications

(4 citation statements)

References 84 publications

(167 reference statements)

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“… 19 On the other hand, BMPRII has a unique, long C-terminal tail with 530 amino acids after the kinase domain. 58 BMPRII has constitutively active kinases and BMPRI has inactive and inducible kinases. Recently, DRAGON, a glycosylphosphatidylinositol-anchored protein, was described as a co-receptor that directly interacts with ligands and receptors to facilitate BMP signaling.…”

Section: Bmp and Its Receptorsmentioning

confidence: 99%

TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

et al. 2015

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Transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-β/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-β (I/II) or BMP receptors activates intracellular downstream Smads, the transducer of TGF-β/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific. Additive, positive, negative, or synergistic effects are observed when TGF-β/BMP interacts with the pathways of MAPK, Wnt, Hedgehog (Hh), Notch, Akt/mTOR, and miRNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-β/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.

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Section: Bmp and Its Receptorsmentioning

confidence: 99%

TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

et al. 2015

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“…Phosphorylation of ActRI takes place in its unique GS domain near the intracellular juxtamembrane regions preceding the serine/threonine kinase domain. ActRI is only activated after being phosphorylated by kinase, whereas ActRII is constitutively activated (287). Once activated, ActRI phosphorylates Smad 2 and Smad 3, which form a heteromeric complex and then incorporate Smad 4.…”

Section: Eamentioning

confidence: 99%

Activin A in Mammalian Physiology

Bloise

Ciarmela

Cruz

et al. 2019

Physiological Reviews

144

129

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Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.

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“…The typical curvature of these fingers creates concave and convex surfaces, namely wrist and knuckle regions, which enable the interaction of Nodal with type I and type II receptor binding epitopes, respectively. In particular, to the wrist region participate, the inner concave surface of the fingers of one monomer and the α ‐helix (H3 helix) and the pre‐helix loop of the other monomer .…”

Section: Introductionmentioning

confidence: 99%

Conformational features and binding affinities to Cripto, ALK7 and ALK4 of Nodal synthetic fragments

et al. 2015

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Nodal, a member of the TGF-β superfamily, is a potent embryonic morphogen also implicated in tumor progression. As for other TGF-βs, it triggers the signaling functions through the interaction with the extracellular domains of type I and type II serine/threonine kinase receptors and with the co-receptor Cripto. Recently, we reported the molecular models of Nodal in complex with its type I receptors (ALK4 and ALK7) as well as with Cripto, as obtained by homology modeling and docking simulations. From such models, potential binding epitopes have been identified. To validate such hypotheses, a series of mutated Nodal fragments have been synthesized. These peptide analogs encompass residues 44-67 of the Nodal protein, corresponding to the pre-helix loop and the H3 helix, and reproduce the wild-type sequence or bear some modifications to evaluate the hot-spot role of modified residues in the receptor binding. Here, we show the structural characterization in solution by CD and NMR of the Nodal peptides and the measurement of binding affinity toward Cripto by surface plasmon resonance. Data collected by both conformational analyses and binding measurements suggest a role for Y58 of Nodal in the recognition with Cripto and confirm that previously reported for E49 and E50. Surface plasmon resonance binding assays with recombinant proteins show that Nodal interacts in vitro also with ALK7 and ALK4 and preliminary data, generated using the Nodal synthetic fragments, suggest that Y58 of Nodal may also be involved in the recognition with these protein partners.

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Antagonism of Activin by Activin Chimeras

Cited by 5 publications

References 84 publications

TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

Activin A in Mammalian Physiology

Conformational features and binding affinities to Cripto, ALK7 and ALK4 of Nodal synthetic fragments

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