title: Constitutively active ALK2 receptor mutants require type II receptor cooperation.
abstract: 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.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Bagarova
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Vonner
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Armstrong
authors.forename: Jan
authors.initials: J
authors.lastname: Börgermann
authors.forename: Carol S C
authors.initials: CS
authors.lastname: Lai
authors.forename: Donna Y
authors.initials: DY
authors.lastname: Deng
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Beppu
authors.forename: Ivan
authors.initials: I
authors.lastname: Alfano
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular; D009221:Myositis Ossificans; D009999:Ossification, Heterotopic / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011651:Pulmonary Artery; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D034741:RNA, Small Interfering; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498943:Acvr1 protein, mouse; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II