Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders
Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders
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DOI：
10.1016/j.bone.2018.03.015
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发表时间：
2018-06-01
期刊：
影响因子：
4.1
通讯作者：
Katagiri, Takenobu
中科院分区：
文献类型：
--
作者：
Machiya, Aiko;Tsukamoto, Sho;Katagiri, Takenobu
ALK2 是骨形态发生蛋白 (BMP) 的跨膜丝氨酸/苏氨酸激酶受体，已在患有进行性骨化性纤维发育不良 (FOP)、弥漫性内在桥脑胶质瘤 (DIPG) 和心脏缺陷等遗传性疾病的患者中发现了各种替代突变。在本研究中，我们鉴定了 ALK2 突变体 R258G、G328V 和 F246Y，这些突变体分别在严重 FOP、DIPG 和异常遗传性骨骼发育不良患者中发现。 R258G和G328V都是功能获得性突变，但F246Y相当于野生型ALK2。我们还检查了抑制因子 FKBP12 对与 FOP 和/或 DIPG 相关的另外 14 个 ALK2 突变的信号转导的影响。 FKBP12 过表达在不同程度上抑制了 13 个 ALK2 突变体诱导的基础信号传导，而 PF197-8L 具有独特的抗性。在 PF197-8L 突变体中，建模的 ALK2 残基 L197 诱导与 FKBP12 中的 D36 残基发生空间冲突，并解离它们的相互作用。 BMP II 型受体的共表达或配体刺激通过破坏突变体 ALK2 和 FKBP12 之间的相互作用来缓解 FKBP12 的抑制。总而言之，FKBP12 结合并抑制与 FOP 和 DIPG 相关的突变 ALK2 蛋白（PF197-8L 除外）。 (C) 2018 作者。由爱思唯尔公司出版
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. (C) 2018 The Authors. Published by Elsevier Inc.