TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs
TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs
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DOI：
10.1038/emboj.2011.54
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发表时间：
2011-04-06
期刊：
影响因子：
11.4
通讯作者：
Hinck, Andrew P.
中科院分区：
文献类型：
--
作者：
Huang, Tao;David, Laurent;Hinck, Andrew P.
转化生长因子（TGF）-β是在调节细胞生长和分化中具有重要作用的二聚体多肽。它们通过组装由两个T β RI：T β RII异二聚体组成的受体异四聚体来发出信号。为了研究两个异二聚体是否自主结合和信号传导，将TGF-β原聚体之一取代以阻断受体结合。取代的二聚体，TGF-β 3 WD，结合TbRII细胞外结构域和招募TbRI与TGF-β 3的亲和力不可区分，但与一半的化学计量。在三种已建立的TGF-β功能测定中，TGF-β 3 WD进一步显示保留TGF-β 3的四分之一到一半的信号传导活性。用GFP标记的受体进行的单分子荧光成像表明，在用TGF-β 3处理后，TbRI和TbRII二聚体的比例可测量地增加，但用TGF-β 3 WD处理后则没有。这些结果提供了证据表明，两个T β RI：T β RII异二聚体结合和信号在一个自主的方式。他们进一步强调了TGF-β是如何从骨形态发生蛋白中分化出来的，骨形态发生蛋白是TGF-β超家族的祖先配体，通过RI：RII：RII异源三聚体发出信号。The EMBO Journal（2011）30，1263-1276. doi：10.1038/daj.2011.54; 2011年3月18日在线发布
Transforming growth factor (TGF)-beta s are dimeric polypeptides that have vital roles in regulating cell growth and differentiation. They signal by assembling a receptor heterotetramer composed of two T beta RI:T beta RII heterodimers. To investigate whether the two heterodimers bind and signal autonomously, one of the TGF-beta protomers was substituted to block receptor binding. The substituted dimer, TGF-beta 3 WD, bound the TbRII extracellular domain and recruited the TbRI with affinities indistinguishable from TGF-beta 3, but with one-half the stoichiometry. TGF-beta 3 WD was further shown to retain one-quarter to one-half the signalling activity of TGF-beta 3 in three established assays for TGF-beta function. Single-molecule fluorescence imaging with GFP-tagged receptors demonstrated a measurable increase in the proportion of TbRI and TbRII dimers upon treatment with TGF-beta 3, but not with TGF-beta 3 WD. These results provide evidence that the two T beta RI:T beta RII heterodimers bind and signal in an autonomous manner. They further underscore how the TGF-beta s diverged from the bone morphogenetic proteins, the ancestral ligands of the TGF-beta superfamily that signal through a RI:RII:RII heterotrimer. The EMBO Journal (2011) 30, 1263-1276. doi: 10.1038/emboj.2011.54; Published online 18 March 2011