孤儿G蛋白偶联受体Gpr175(Tpra40)通过调节cAMP水平增强刺猬信号通路。

The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels.

作者信息

Singh Jaskirat, Wen Xiaohui, Scales Suzie J

机构信息

From the Department of Molecular Biology, Genentech, South San Francisco, California 94080.

From the Department of Molecular Biology, Genentech, South San Francisco, California 94080

出版信息

J Biol Chem. 2015 Dec 4;290(49):29663-75. doi: 10.1074/jbc.M115.665810. Epub 2015 Oct 8.

Abstract

The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway.

摘要

刺猬(Hh)信号通路在许多发育器官的脊椎动物胚胎组织模式形成中起着至关重要的作用。信号传导主要发生在初级纤毛中,由G蛋白偶联受体(GPCR)样蛋白 smoothened 进入纤毛引发,并在转录因子Gli家族进入细胞核后通过它们最终导致基因转录。在这里,我们鉴定出一种孤儿GPCR,即Gpr175(也称为Tpra1或Tpra40:跨膜蛋白,脂肪细胞相关1或40 kDa),它在Hh刺激后也定位于初级纤毛,并正向调节Hh信号传导。相互作用实验表明Gpr175作用于PKA水平且在异源三聚体G蛋白的Gαi组分上游,Gαi本身定位于纤毛并可调节Hh信号传导。Gpr175或Gαi1的缺失导致细胞内cAMP水平升高以及Gli3加工成其阻遏物形式。因此,我们提出与Gαi1偶联的Gpr175通常在Hh刺激时发挥作用,抑制腺苷酸环化酶产生cAMP,从而通过关闭PKA活性进而减少Gli3阻遏物的形成来最大化信号传导。综上所述,我们的数据表明Gpr175是Hh信号通路的一种新型正向调节因子。

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