The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor.
The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor.
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DOI：
10.1083/jcb.200612046
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发表时间：
2007-07-16
期刊：
影响因子：
--
通讯作者：
Théret N
中科院分区：
文献类型：
--
作者：
Atfi A;Dumont E;Colland F;Bonnier D;L'helgoualc'h A;Prunier C;Ferrand N;Clément B;Wewer UM;Théret N
转化生长因子-β（Transforming growth factor-β，TGF-β）通过两种类型的Ser/Thr跨膜受体调节多种生物学过程：TGF-β I型受体和TGF-β II型受体（TβRII）。在配体结合后，由TβRII激活的TGF-β I型受体将信号传播到Smad蛋白，Smad蛋白介导TGF-β靶基因的激活。在这项研究中，我们确定了ADAM 12（一种去整合素和金属蛋白酶12）作为TGF-β信号通路的一个组成部分，通过与TβRII结合发挥作用。我们发现ADAM 12通过一种不依赖于其蛋白酶活性的机制来促进TGF-β信号的激活，包括Smad 2的磷酸化、Smad 2与Smad 4的结合以及转录激活。此外，ADAM 12诱导TβRII在早期内体囊泡中的积累，并可能通过抑制TβRII与Smad 7的结合来稳定TβRII蛋白。这些结果将ADAM 12定义为TβRII的新伴侣，有助于其运输到早期内体，在早期内体中启动Smad通路的激活。
Transforming growth factor-β (TGF-β) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-β type I receptor and the TGF-β type II receptor (TβRII). Upon ligand binding, TGF-β type I receptor activated by TβRII propagates signals to Smad proteins, which mediate the activation of TGF-β target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-β signaling pathway that acts through association with TβRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-β signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TβRII in early endosomal vesicles and stabilizes the TβRII protein presumably by suppressing the association of TβRII with Smad7. These results define ADAM12 as a new partner of TβRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.
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