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Bone. 2018 Jun;111:101-108. doi: 10.1016/j.bone.2018.03.015. Epub 2018 Mar 15.

Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders.

Author information

1
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, Saitama, Japan.
2
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Project of Clinical and Basic Research for FOP, Saitama Medical University, Saitama, Japan.
3
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
4
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Ivy Dental Clinic, Fukuoka, Japan.
5
Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, Saitama, Japan.
6
Structural Genomics Consortium, University of Oxford, Oxford, UK.
7
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Project of Clinical and Basic Research for FOP, Saitama Medical University, Saitama, Japan. Electronic address: katagiri@saitama-med.ac.jp.

Abstract

Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2. We also examined the effect of the suppressor FKBP12 on the signal transduction of a further 14 ALK2 mutations associated with FOP and/or DIPG. To varying extents FKBP12 over-expression suppressed the basal signaling induced by thirteen of the ALK2 mutants, whereas PF197-8L was uniquely resistant. In the PF197-8L mutant, the modelled ALK2 residue L197 induced a steric clash with the D36 residue in FKBP12 and dissociated their interaction. The co-expression of BMP type II receptors or stimulation with ligands relieved the suppression by FKBP12 by disrupting the interaction between mutant ALK2 and FKBP12. Taken together, FKBP12 binds to and suppresses mutant ALK2 proteins associated with FOP and DIPG, except for PF197-8L.

KEYWORDS:

Activin receptor-like kinase 2 (ALK2); Bone morphogenetic proteins (BMPs); Diffuse intrinsic pontine glioma (DIPG); FKBP12; Fibrodysplasia ossificans progressiva (FOP); Heterotopic ossification; Signal transduction

PMID:
29551750
DOI:
10.1016/j.bone.2018.03.015
[Indexed for MEDLINE]
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