Functional characterization of a unique mutant of ALK2, p.K400E, that is associated with a skeletal disorder, diffuse idiopathic skeletal hyperostosis.
Functional characterization of a unique mutant of ALK2, p.K400E, that is associated with a skeletal disorder, diffuse idiopathic skeletal hyperostosis.
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DOI：
10.1016/j.bone.2020.115410
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发表时间：
2020-05
期刊：
影响因子：
4.1
通讯作者：
S. Tsukamoto;Mai Kuratani;T. Katagiri
中科院分区：
文献类型：
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作者：
S. Tsukamoto;Mai Kuratani;T. Katagiri
骨形态发生蛋白（BMP）信号转导调节骨骼组织的生理和病理发育。激活素受体样激酶2（ALK 2）是BMP I型跨膜丝氨酸/苏氨酸激酶受体。最近，在患有弥漫性特发性骨肥厚（DISH）的患者中发现ALK 2中的p.K400E突变，DISH是一种以脊柱韧带和附着点钙化和骨化为特征的疾病。我们在此报告ALK 2 p.K400E在体外的功能表征。过表达ALK 2 p.K400E的细胞响应成骨BMP配体激活BMP信号传导。然而，ALK 2 p.K400 E不被非成骨配体激活素A激活。BMP II型受体的共表达进一步增强了通过ALK 2 p.K400 E的BMP信号传导。II型受体增加ALK 2 p.K400E的磷酸化水平，表明ALK 2 p.K400E是BMP II型受体激酶的超敏突变体。我们的研究结果表明，DISH中的病理性钙化和骨化是由过度激活的BMP信号传导引起的，通过ALK 2 p.K400 E，II型受体响应成骨BMP而不是激活素A增强BMP信号传导。
Bone morphogenetic protein (BMP) signaling regulates the physiological and pathological development of skeletal tissues. Activin receptor-like kinase 2 (ALK2) is a BMP type I transmembrane serine/threonine kinase receptor. Recently, a p.K400E mutation was found in ALK2 in a patient with diffuse idiopathic skeletal hyperostosis (DISH), which is a disorder characterized by calcification and ossification of spinal ligaments and entheses. We report here the functional characterization of ALK2 p.K400E in vitro. Cells overexpressing ALK2 p.K400E activated BMP signaling in response to osteogenic BMP ligands. However, ALK2 p.K400E was not activated by a nonosteogenic ligand, Activin A. BMP signaling through ALK2 p.K400E was further enhanced by the coexpression of a BMP type II receptor. The type II receptor increased the phosphorylation level of ALK2 p.K400E, suggesting that ALK2 p.K400E is a hypersensitive mutant to the BMP type II receptor kinases. Our findings suggest that pathological calcification and ossification in DISH are caused by overactivated BMP signaling through ALK2 p.K400E enhanced by type II receptors in response to osteogenic BMPs rather than Activin A.