Constitutively active ALK2 receptor mutants require type II receptor cooperation
| Autor: | Kelli A. Armstrong, Panagis Filippakopoulos, Jana Bagarova, Petra Knaus, Ashley J. Vonner, Nicholas W. Morrell, Yuji Mishina, I. Alfano, Paul B. Yu, Alex N. Bullock, Donna Y. Deng, Hideyuki Beppu, Carol S. Lai, Jan Börgermann |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Activin Receptors Type II Mice Transgenic Pulmonary Artery Biology ACVR1 Bone Morphogenetic Protein Receptors Type II Bone morphogenetic protein Muscle Smooth Vascular Mice Internal medicine medicine Animals Bone morphogenetic protein receptor RNA Small Interfering Author Correction Receptor Molecular Biology Janus kinase 1 Ossification Heterotopic Cell Biology Activin receptor Articles Protein Structure Tertiary BMPR2 Cell biology Endocrinology Myositis Ossificans Bone Morphogenetic Proteins RNA Interference Signal transduction Activin Receptors Type I Signal Transduction |
| Zdroj: | Molecular and cellular biology. 33(12) |
| ISSN: | 1098-5549 0270-7306 |
| Popis: | Constitutively activating mutations in receptor kinases recruit downstream effector pathways independently of upstream signaling, with consequences ranging from developmental syndromes to cancer. Classic fibrodysplasia ossificans progressiva (FOP) is a congenital syndrome resulting from highly conserved activating mutations of the glycine-serine-rich (GS) regulatory domain of ACVR1, encoding bone morphogenetic protein (BMP) type I receptor ALK2, which lead to inappropriate signaling and heterotopic ossification of soft tissues. It is unclear if constitutively active mutant ALK2 receptors (caALK2) can function independently of signaling complexes with type II receptors and ligands. We found that ablation of BmpRII and ActRIIa abrogated BMP ligand-mediated and caALK2-mediated signaling and transcription in cells and disrupted caALK2-induced heterotopic ossification in mice. Signaling via GS domain ALK2 mutants could be restored by the expression of either BMP type II receptor. The contribution of BMP type II receptors was independent of their ligand-binding or kinase function but was dependent upon an intact cytoplasmic domain. These data demonstrate that GS domain ALK2 mutants act independently of upstream signaling but may require a nonenzymatic scaffolding function provided by type II receptors to form functional, apparently ligand-independent signaling complexes. These findings define the minimal requirements for signaling of GS domain ALK2 mutants, with implications for the therapeutic targeting of their activity in disease. |
| Databáze: | OpenAIRE |
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