Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.
Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.
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DOI：
10.1371/journal.pbio.0040115
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发表时间：
2006-04
期刊：
影响因子：
9.8
通讯作者：
Nusse R
中科院分区：
文献类型：
--
作者：
Mikels AJ;Nusse R
Wnts 包含一大类分泌蛋白，控制着胚胎模式、细胞生长、迁移和分化等基本发育过程。在最广为人知的“经典”Wnt 信号通路中，Wnt 与 Frizzled 受体结合诱导 β-catenin 蛋白稳定并进入细胞核，与 T 细胞因子/淋巴增强因子转录因子复合，从而影响靶基因的转录。除了经典通路之外，其他几种 Wnt 信号通路的证据也已经积累起来，特别是 Wnt5a，因此它被归类为非经典 Wnt 家族成员。为了研究 Wnt 蛋白信号传导的替代机制，我们将 Wnt5a 蛋白纯化至均质。我们发现纯化的 Wnt5a 以剂量依赖性方式抑制 Wnt3a 蛋白诱导的经典 Wnt 信号传导，不是通过影响 β-连环蛋白水平，而是通过下调 β-连环蛋白诱导的报告基因表达。 Wnt5a 信号由孤儿酪氨酸激酶 Ror2 介导，对百日咳毒素不敏感，并且不影响细胞钙水平。我们发现，除了其抑制功能外，Wnt5a 还可以在适当的卷曲受体 (Frizzled 4) 存在的情况下激活 β-连环蛋白信号传导。因此，这项研究首次表明，单个 Wnt 配体可以通过激活两个不同的受体来启动离散的信号传导途径。基于这些和其他观察结果，我们提出了一个模型，其中受体上下文决定 Wnt 信号输出。在该模型中，不同 Wnt 家族成员的信号传导本质上不是由 Wnt 蛋白本身调节，而是由受体可用性调节。历史上相互矛盾的数据阻碍了对 Wnt 蛋白信号传导的理解。作者通过使用纯化的 Wnt5a 来探测其激活的信号通路，从而协调了之前有关 Wnt 信号传导的发现。
The Wnts comprise a large class of secreted proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation. In the most well-understood “canonical” Wnt signaling pathway, Wnt binding to Frizzled receptors induces β-catenin protein stabilization and entry into the nucleus, where it complexes with T-cell factor/lymphoid enhancer factor transcription factors to affect the transcription of target genes. In addition to the canonical pathway, evidence for several other Wnt signaling pathways has accumulated, in particular for Wnt5a, which has therefore been classified as a noncanonical Wnt family member. To study the alternative mechanisms by which Wnt proteins signal, we purified the Wnt5a protein to homogeneity. We find that purified Wnt5a inhibits Wnt3a protein–induced canonical Wnt signaling in a dose-dependent manner, not by influencing β-catenin levels but by downregulating β-catenin–induced reporter gene expression. The Wnt5a signal is mediated by the orphan tyrosine kinase Ror2, is pertussis toxin insensitive, and does not influence cellular calcium levels. We show that in addition to its inhibitory function, Wnt5a can also activate β-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. Thus, this study shows for the first time that a single Wnt ligand can initiate discrete signaling pathways through the activation of two distinct receptors. Based on these and additional observations, we propose a model wherein receptor context dictates Wnt signaling output. In this model, signaling by different Wnt family members is not intrinsically regulated by the Wnt proteins themselves but by receptor availability. Understanding signaling by Wnt proteins has been hampered by a history of conflicting data. The authors reconcile previous findings concerning Wnt signaling by using purified Wnt5a to probe the signaling pathways it activates.
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DOI：
10.1073/pnas.96.7.3546
发表时间：
1999-03-30
影响因子：
11.1
作者：
Hsieh, JC;Rattner, A;Nathans, J
通讯作者：
Nathans, J
影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
64.8
作者：
Jordan, BA;Devi, LA
通讯作者：
Devi, LA
影响因子：
9.2
作者：
Marlow, F;Topczewski, J;Solnica-Krezel, L
通讯作者：
Solnica-Krezel, L
影响因子：
11.4
作者：
Kühl, M;Sheldahl, LC;Moon, RT
通讯作者：
Moon, RT