Hildebrand Laura, Stange Katja, Deichsel Alexandra, Gossen Manfred, Seemann Petra
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany; Leibniz Institute for Farm Animal Biology, Institute for Muscle Biology and Growth, Dummerstorf, Germany.
Cell Signal. 2017 Jan;29:23-30. doi: 10.1016/j.cellsig.2016.10.001. Epub 2016 Oct 4.
Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. In this study we compared the signalling responses of ACVR1 and ACVR1 to different ligands. ACVR1, but not ACVR1 inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1, but enhanced by ACVR1. In comparison, BMP6 or BMP7 activated ACVR1 and caused a hyper-activation of ACVR1. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1. We conclude that the FOP mutation ACVR1 is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients.
进行性骨化性纤维发育不良（FOP）患者会出现异位骨形成，这种情况在患者一生中都会持续发展，并导致严重的运动受限。该疾病的病因是1型激活素A受体（ACVR1）的点突变，其中p.R206H最为常见。在本研究中，我们比较了ACVR1和ACVR1对不同配体的信号转导反应。ACVR1而非ACVR1以不依赖配体结合域的方式抑制BMP2或BMP4的BMP信号。同样，受体BMPR1A或BMPR1B的基础BMP信号活性被ACVR1抑制，但被ACVR1增强。相比之下，BMP6或BMP7激活ACVR1并导致ACVR1过度激活。这些效应依赖于完整的配体结合域。最后，对激活素A在FOP中的新功能进行了测试，发现其激活ACVR1依赖于配体结合域。我们得出结论，FOP突变型ACVR1对多种天然配体更为敏感。突变受体显然失去了与配体和共受体的一些重要抑制性相互作用，从而导致配体依赖性信号增强，并如患者中所观察到的那样刺激异位骨形成。
