ArticleMolecular endocrinology (Baltimore, Md.)2015
Mutant activin-like kinase 2 in fibrodysplasia ossificans progressiva are activated via T203 by BMP type II receptors.
Article in Molecular endocrinology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 26 citations in OpenAlex.
- Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders.Nature communications · 2023Article
- Characterization of Fibrodysplasia Ossificans Progessiva relevant Acvr1/Acvr2 Activin receptors in medaka (Oryzias latipes).PloS one · 2023Article
- Accumulated Knowledge of Activin Receptor-Like Kinase 2 (ALK2)/Activin A Receptor, Type 1 (ACVR1) as a Target for Human Disorders.Biomedicines · 2021Review
- Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling.International journal of molecular sciences · 2020Article
- The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator.Bioscience reports · 2019Review
- Discovery of Heterotopic Bone-Inducing Activity in Hard Tissues and the TGF-β Superfamily.International journal of molecular sciences · 2018Review
- Recent Topics in Fibrodysplasia Ossificans Progressiva.Endocrinology and metabolism (Seoul, Korea) · 2018Review
- Review
- Bone Morphogenetic Proteins.Cold Spring Harbor perspectives in biology · 2016Review
- A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2016Article
- ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.Science translational medicine · 2015Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as the skeletal muscles. FOP has been shown to be caused by gain-of-function mutations in activin receptor-like kinase (ALK)-2, which is a type I receptor for bone morphogenetic proteins (BMPs). In the present study, we examined the molecular mechanisms that underlie the activation of intracellular signaling by mutant ALK2. Mutant ALK2 from FOP patients enhanced the activation of intracellular signaling by type II BMP receptors, such as BMPR-II and activin receptor, type II B, whereas that from heart disease patients did not. This enhancement was dependent on the kinase activity of the type II receptors. Substitution mutations at all nine serine and threonine residues in the ALK2 glycine- and serine-rich domain simultaneously inhibited this enhancement by the type II receptors. Of the nine serine and threonine residues in ALK2, T203 was found to be critical for the enhancement by type II receptors. The T203 residue was conserved in all of the BMP type I receptors, and these residues were essential for intracellular signal transduction in response to ligand stimulation. The phosphorylation levels of the mutant ALK2 related to FOP were higher than those of wild-type ALK2 and were further increased by the presence of type II receptors. The phosphorylation levels of ALK2 were greatly reduced in mutants carrying a mutation at T203, even in the presence of type II receptors. These findings suggest that the mutant ALK2 related to FOP is enhanced by BMP type II receptors via the T203-regulated phosphorylation of ALK2.
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