Dpr1和Dpr2在调节Wnt/TGF-β信号中的作用
摘要
Dapper(Dpr)蛋白家族中不同的成员:Dapper1(Dpr1)和Dapper2(Dpr2)蛋白,在先前爪蟾的研究以及我们克隆得到的斑马鱼Dapper2蛋白在斑马鱼中的研究中已经发现,它们能够分别调控Wnt和TGFβ信号通路。为了能够对Dapper这一家族蛋白在哺乳动物中的功能做进一步的研究,我们克隆了斑马鱼Dapper2蛋白在小鼠中的同源蛋白mDpr2并对其在调控TGFβ信号通路中的作用进行了研究。我们的研究发现,和斑马鱼zDpr2的功能相类似,在哺乳动物细胞中过量表达mDpr2蛋白能够诱导TGFβI型受体的降解,从而抑制TGFβ诱导的下游报告基因的表达。特异性抑制内源mDpr2的RNA干扰也能上调TGFβ报告基因的表达。这些研究结果揭示了Dpr2作为进化上保守的TGFβ逆调控因子而存在。
Wnt信号在胚胎发育和癌症发生中起很重要的作用,爪蟾中的Dpr蛋白作为Dishevelled(Dvl)的结合蛋白被发现,并证实在Wnt信号中起作用。但其哺乳动物(人与小鼠)的同源蛋白Dpr1,是否也起到相类似的作用,是否如Dpr2蛋白一样能够调控TGFβ信号,都不得而知。因此,我们克隆得到了人和小鼠的Dapper1基因并发现,与Dpr2蛋白不同,哺乳动物的Dpr1基因能够明显的抑制经典Wnt信号通路和非经典的Wnt信号通路。通过相互作用区段的分析,我们鉴定了Dpr1蛋白和Dvl2蛋白的相互作用区段主要是通过Dpr1蛋白的C端区域结合Dvl2蛋白的DEP结构区域。利用Wnt信号的报告基因,我们发现,Dpr1对Wnt信号呈现的抑制作用需要该蛋白各个区段一起的参与,单独表达Dpr1的C端225个氨基酸区段对Wnt报告基因表现出来的激活证明了该区段是Dpr1的显形失活区域。深入的研究我们发现,Dpr1蛋白能够通过结合Dvl2蛋白诱导其通过溶酶体降解。特异性抑制内源Dpr1的RNA干扰不仅能够上调Wnt信号,而且能够增加内源Dvl2的蛋白表达。从而,我们的工作也证实了Dpr1是进化上保守的Wnt信号的抑制因子。
为了深入地研究Dapper家族蛋白的生物学功能,本课题克隆了Dpr1/Dpr2在酵母中表达的诱饵蛋白,利用人胎儿脑文库cDNA完成了酵母双杂交,为以后的研究奠定了一定的基础。
Dapper1 and Dapper2, two divergent members of the Dapper family, have been suggested to modulate Wnt and TGFβ/Nodal signaling in Xenopus and zebrafish. To get a better understanding of Dapper function in mammals, we have cloned the mouse ortholog of zebrafish Dapper2, mDpr2 and investigated its function in regulating TGFβsignaling activity. Here, we showed that, like zebrafish Dapper2, overexpression of mDpr2 inhibited the TGFβ-induced expression of the Smad-responsive reporters and targeted TGFβtype I receptor ALK5 for degradation in mammalian cells, and knocking down of Dpr2 by RNA interference up-regulates TGFβreporter gene activity, which implying that mDpr2 may have an intrinsic in vivo activity similar to fish Dapper2 activity. Our data indicate that the function of Dpr2 as a negative regulator of the TGFβ/Nodal signal pathway is evolutionally conserved, at least in part, in fish and mammals.
Wnt signaling plays pivotal roles in the regulation of embryogenesis and cancer development. Xenopus Dapper (Dpr) was identified as an interacting protein for Dishevelled (Dvl), a Wnt signaling mediator, and modulates Wnt signaling. However, it is largely unclear whether and how Dpr1 regulates Wnt signaling and whether like Dpr2, it still has inhibitory effect on TGFβsignaling. Here, we firstly cloned the human Dapper1 and mouse Dapper1 gene and present evidence that human Dpr1, the ortholog of Xenopus Dpr, inhibits both canonical and none-canonical Wnt signaling. We have identified the regions responsible for the Dpr-Dvl interaction in both proteins and found that the interaction interface is formed between the DEP (Dishevelled, Egl-10, and pleckstrin) domain of Dvl and the central and the C-terminal regions of Dpr1. The inhibitory function of human Dpr1 requires both its N and C terminus. Overexpression of the C-terminal region corresponding to the last 225 amino acids of Dpr1, in contrast to wild-type Dpr1, enhances Wnt signaling, suggesting a dominant negative function of this region. Furthermore, we have shown that Dpr1 induces Dvl degradation via a lysosome inhibitor-sensitive and proteasome inhibitor-insensitive mechanism. Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein. Taken together, our data indicate that the inhibitory activity of Dpr on Wnt signaling is conserved from Xenopus to human and that Dpr1 antagonizes Wnt signaling by inducing Dvl degradation.
To deeply elucidate the biological function of Dapper protein family. Yeast two hybrid were carried out by using Dpr1/Dpr2 protein as baits and Fetal brain cDNA as libray. These findings provides basis for further study.
Wnt信号在胚胎发育和癌症发生中起很重要的作用,爪蟾中的Dpr蛋白作为Dishevelled(Dvl)的结合蛋白被发现,并证实在Wnt信号中起作用。但其哺乳动物(人与小鼠)的同源蛋白Dpr1,是否也起到相类似的作用,是否如Dpr2蛋白一样能够调控TGFβ信号,都不得而知。因此,我们克隆得到了人和小鼠的Dapper1基因并发现,与Dpr2蛋白不同,哺乳动物的Dpr1基因能够明显的抑制经典Wnt信号通路和非经典的Wnt信号通路。通过相互作用区段的分析,我们鉴定了Dpr1蛋白和Dvl2蛋白的相互作用区段主要是通过Dpr1蛋白的C端区域结合Dvl2蛋白的DEP结构区域。利用Wnt信号的报告基因,我们发现,Dpr1对Wnt信号呈现的抑制作用需要该蛋白各个区段一起的参与,单独表达Dpr1的C端225个氨基酸区段对Wnt报告基因表现出来的激活证明了该区段是Dpr1的显形失活区域。深入的研究我们发现,Dpr1蛋白能够通过结合Dvl2蛋白诱导其通过溶酶体降解。特异性抑制内源Dpr1的RNA干扰不仅能够上调Wnt信号,而且能够增加内源Dvl2的蛋白表达。从而,我们的工作也证实了Dpr1是进化上保守的Wnt信号的抑制因子。
为了深入地研究Dapper家族蛋白的生物学功能,本课题克隆了Dpr1/Dpr2在酵母中表达的诱饵蛋白,利用人胎儿脑文库cDNA完成了酵母双杂交,为以后的研究奠定了一定的基础。
Dapper1 and Dapper2, two divergent members of the Dapper family, have been suggested to modulate Wnt and TGFβ/Nodal signaling in Xenopus and zebrafish. To get a better understanding of Dapper function in mammals, we have cloned the mouse ortholog of zebrafish Dapper2, mDpr2 and investigated its function in regulating TGFβsignaling activity. Here, we showed that, like zebrafish Dapper2, overexpression of mDpr2 inhibited the TGFβ-induced expression of the Smad-responsive reporters and targeted TGFβtype I receptor ALK5 for degradation in mammalian cells, and knocking down of Dpr2 by RNA interference up-regulates TGFβreporter gene activity, which implying that mDpr2 may have an intrinsic in vivo activity similar to fish Dapper2 activity. Our data indicate that the function of Dpr2 as a negative regulator of the TGFβ/Nodal signal pathway is evolutionally conserved, at least in part, in fish and mammals.
Wnt signaling plays pivotal roles in the regulation of embryogenesis and cancer development. Xenopus Dapper (Dpr) was identified as an interacting protein for Dishevelled (Dvl), a Wnt signaling mediator, and modulates Wnt signaling. However, it is largely unclear whether and how Dpr1 regulates Wnt signaling and whether like Dpr2, it still has inhibitory effect on TGFβsignaling. Here, we firstly cloned the human Dapper1 and mouse Dapper1 gene and present evidence that human Dpr1, the ortholog of Xenopus Dpr, inhibits both canonical and none-canonical Wnt signaling. We have identified the regions responsible for the Dpr-Dvl interaction in both proteins and found that the interaction interface is formed between the DEP (Dishevelled, Egl-10, and pleckstrin) domain of Dvl and the central and the C-terminal regions of Dpr1. The inhibitory function of human Dpr1 requires both its N and C terminus. Overexpression of the C-terminal region corresponding to the last 225 amino acids of Dpr1, in contrast to wild-type Dpr1, enhances Wnt signaling, suggesting a dominant negative function of this region. Furthermore, we have shown that Dpr1 induces Dvl degradation via a lysosome inhibitor-sensitive and proteasome inhibitor-insensitive mechanism. Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein. Taken together, our data indicate that the inhibitory activity of Dpr on Wnt signaling is conserved from Xenopus to human and that Dpr1 antagonizes Wnt signaling by inducing Dvl degradation.
To deeply elucidate the biological function of Dapper protein family. Yeast two hybrid were carried out by using Dpr1/Dpr2 protein as baits and Fetal brain cDNA as libray. These findings provides basis for further study.
引文
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