Ror2/Frizzled Complex Mediates Wnt5a-Induced AP-1 Activation by Regulating Dishevelled Polymerization
Ror2/Frizzled Complex Mediates Wnt5a-Induced AP-1 Activation by Regulating Dishevelled Polymerization
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DOI：
10.1128/mcb.00177-10
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发表时间：
2010-07-01
影响因子：
5.3
通讯作者：
Minami, Yasuhiro
中科院分区：
文献类型：
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作者：
Nishita, Michiru;Itsukushima, Sumiyo;Minami, Yasuhiro
受体酪氨酸激酶Ror2作为Wnt5a的受体或辅助受体，介导Wnt5a诱导的Wnt/JNK途径的激活和β-连环素依赖的典型Wnt途径的抑制。然而，关于Ror2如何与另一个受体成分(S)合作介导Wnt5a信号转导，人们知之甚少。我们在这里表明，Ror2调节Wnt5a诱导的DVL聚合，并且这种Ror2介导的DVL调节不依赖于Ror2的细胞质区域。ROR2可以通过其胞外富含半胱氨酸的结构域与Frizzled7(Fz7)结合，形成一个受体复合体，在Wnt5a刺激后调节DVL和激活AP-1启动子。抑制Fz7的表达确实会抑制Wnt5a诱导的DVL聚合和AP-1的激活。有趣的是，DVL的DIX和DEP结构域对于DVL聚合和Wnt5a刺激后随后的AP-1激活都是必不可少的。我们进一步表明，聚合的DVL与rac1共定位，而rac1的表达抑制了Wnt5a诱导的AP-1的激活。总之，我们的结果表明，Ror2/Fz受体复合体通过调节DVL的聚合在Wnt5a/rac1/AP-1途径中发挥重要作用。
The receptor tyrosine kinase Ror2 acts as a receptor or coreceptor for Wnt5a to mediate Wnt5a-induced activation of the Wnt/JNK pathway and inhibition of the beta-catenin-dependent canonical Wnt pathway. However, little is known about how Ror2 cooperates with another receptor component(s) to mediate Wnt5a signaling. We show here that Ror2 regulates Wnt5a-induced polymerization of Dishevelled (Dvl) and that this Ror2-mediated regulation of Dvl is independent of the cytoplasmic region of Ror2. Ror2 can associate with Frizzled7 (Fz7) via its extracellular cysteine-rich domain to form a receptor complex that is required for the regulation of Dvl and activation of the AP-1 promoter after Wnt5a stimulation. Suppressed expression of Fz7 indeed results in the inhibition of Wnt5a-induced polymerization of Dvl and AP-1 activation. Interestingly, both the DIX and the DEP domains of Dvl are indispensable for Dvl polymerization and subsequent AP-1 activation after Wnt5a stimulation. We further show that polymerized Dvl is colocalized with Rac1 and that suppressed expression of Rac1 inhibits Wnt5a-induced AP-1 activation. Collectively, our results indicate that Ror2/Fz receptor complex plays an important role in the Wnt5a/Rac1/AP-1 pathway by regulating the polymerization of Dvl.