Hyperactive BMP signaling induced by ALK2(R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva.
Hyperactive BMP signaling induced by ALK2(R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva.
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DOI：
10.1002/dvdy.22779
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发表时间：
2012-01
影响因子：
2.5
通讯作者：
Wharton, Kristi A.
中科院分区：
文献类型：
--
作者：
Le, Viet Q.;Wharton, Kristi A.
关键词：
进行性骨化纤维发育不良（FOP）是一种常染色体显性骨骼疾病，其特征是广泛和衰弱的骨形成取代软结缔组织。所有与FOP相关的突变都指向BMP I型受体ALK2，绝大多数患者具有ALK2R206H突变，导致信号传导过度活跃。在这里，我们发现人类ALK2R206H在果蝇细胞培养和体内都表现出过度活跃的信号传导。与脊椎动物中alk2r206h诱导的信号传导一样，我们发现在果蝇中信号传导的增加也是与配体无关的。利用果蝇系统来确定这种过度活跃所需的因素，我们确定了II型受体是突变型ALK2R206H受体信号传导的关键决定因素。此外，我们发现野生型ALK2受体可以拮抗和促进BMP信号传导。由于FOP典型的杂合性，这种双重功能特别令人感兴趣，因为野生型ALK2的两种不同行为之间的相互作用可以通过过度活跃的ALK2R206H突变受体的存在而改变。我们提出我们的工作作为一个令人信服的例子，使用果蝇作为一个模式生物来研究复杂的人类综合征，如FOP的分子基础。
Fibrodysplasia Ossificans Progressiva (FOP) is an autosomal dominant skeletal disorder characterized by widespread and debilitating bone formation in place of soft connective tissue. All mutations associated with FOP map to the BMP type I receptor, ALK2, with the vast majority of patients possessing the ALK2R206H mutation which results in hyperactive signaling. Here, we show that human ALK2R206H exhibits hyperactive signaling both in Drosophila cell culture and in vivo. As true for ALK2R206H–induced signaling in vertebrates, we find that the increase in signaling is also ligand-independent in Drosophila. Using the Drosophila system to identify factors required for this hyperactivity, we identified the type II receptor as a key determinant for mutant ALK2R206H receptor signaling. In addition, we found that the wild-type ALK2 receptor can antagonize, as well as promote, BMP signaling. Due to the heterozygosity typical of FOP, this dual function is of particular interest given that the interplay between the two disparate behaviors of wild-type ALK2 could be shifted by the presence of the hyperactive ALK2R206H mutant receptors. We present our work as a compelling example for the use of Drosophila as a model organism to study the molecular underpinnings of a complex human syndrome such as FOP.
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DOI：
10.1073/pnas.0602558103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Allendorph, George P.;Vale, Wylie W.;Choe, Senyon
通讯作者：
Choe, Senyon
影响因子：
11.4
作者：
Chen, YG;Liu, F;Massague, J
通讯作者：
Massague, J
影响因子：
2.4
作者：
Fritsch, Cornelia;Lanfear, Robert;Ray, Robert P.
通讯作者：
Ray, Robert P.
影响因子：
--
作者：
Clarke, TR;Hoshiya, Y;Donahoe, PK
通讯作者：
Donahoe, PK
影响因子：
4.8
作者：
Fukuda, Toru;Kohda, Masakazu;Katagiri, Takenobu
通讯作者：
Katagiri, Takenobu