Cell-type specific regulation of myostatin signaling
Cell-type specific regulation of myostatin signaling
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DOI：
10.1096/fj.11-191189
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发表时间：
2012-04-01
期刊：
影响因子：
4.8
通讯作者：
Hoogaars, Willem M.
中科院分区：
文献类型：
--
作者：
Kemaladewi, Dwi U.;de Gorter, David J. J.;Hoogaars, Willem M.
转化生长因子-β家族成员myostatin是成肌细胞、脂肪细胞和成纤维细胞生长分化的重要调节因子，但其信号转导机制尚不清楚。因此，我们确定了肌抑制素I型受体激活素受体样激酶-4(ALK4)和-5(ALK5)及其不同的辅助受体在C2C12成肌细胞、C3H10T1/2间充质干细胞和3T3-L1成纤维细胞以及原代成肌细胞和成纤维细胞中的作用。我们进行了siRNA介导的每个受体的敲除，并以非靶向siRNA为对照，使用Smad3依赖的荧光素酶和Smad2磷酸化实验来测量信号活性。我们发现，在成肌细胞中，Myostatin利用ALK4，而在非肌源性细胞中，它偏爱Alk5。值得注意的是，我们的结果表明，辅助受体Cripto在成肌细胞中表达，但在非肌源性细胞中不表达，并且它调节肌肉生长抑素的活性。更具体地说，myostatin需要成肌细胞中的Cripto，而Cripto抑制激活素的活性，并且转化生长因子-β信号不依赖于Cripto。CRIPTO介导的myostatin信号转导依赖于表皮生长因子(EGF)样域和CRIPTO-FRL1隐蔽结构域，而激活素信号转导信号仅由CFCF域决定。此外，Cripto下调促进成肌细胞分化，显示其在肌肉抑制素信号转导中的重要性。总之，我们的结果确定了一种分子机制，可以解释肌肉生长抑素和其他转化生长因子-β家族成员对细胞类型信号的特殊调控。-Kemaladewi，D.U，de Gorter，D.J.，Aartsma-Rus，A.，van Omman，G.-J.ten Dijke，P.，‘t Hoen，P.A.，Hoogaars，W.M.肌肉生长抑制素信号的细胞类型特殊调节。《FASE B J.26,1462-1472》(2012)。www.Fasebj.org
The transforming growth factor (TGF)-beta family member myostatin is an important regulator of myoblast, adipocyte, and fibroblast growth and differentiation, but the signaling mechanisms remain to be established. We therefore determined the contribution of myostatin type I receptors activin receptor-like kinase-4 (ALK4) and -5 (ALK5) and different coreceptors in C2C12 myoblasts, C3H10T1/2 mesenchymal stem cells, and 3T3-L1 fibroblasts, as well as in primary myoblast and fibroblasts. We performed siRNA-mediated knockdown of each receptor and measured signaling activity using Smad3-dependent luciferase and Smad2 phosphorylation assays with nontargeting siRNA as control. We find that myostatin utilizes ALK4 in myoblasts, whereas it has a preference for ALK5 in nonmyogenic cells. Notably, our results show that coreceptor Cripto is expressed in myoblasts but not in the nonmyogenic cells and that it regulates myostatin activity. More specifically, myostatin requires Cripto in myoblasts, whereas Cripto represses activin activity and TGF-beta signaling is Cripto independent. Cripto-mediated myostatin signaling is dependent on both epidermal growth factor (EGF)-like and Cripto-FRL1-cryptic (CFC) domains, whereas activin signaling is solely conferred by the CFC domain. Furthermore, Cripto down-regulation enhances myoblast differentiation, showing its importance in myostatin signaling. Together, our results identify a molecular mechanism that explains the cell-type specific aspects of signaling by myostatin and other TGF-beta family members.-Kemaladewi, D. U., de Gorter, D. J. J., Aartsma-Rus, A., van Ommen, G.-J. ten Dijke, P., 't Hoen, P. A., Hoogaars, W. M. Cell-type specific regulation of myostatin signaling. FASEB J. 26, 1462-1472 (2012). www.fasebj.org