G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog.
G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog.
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DOI：
10.1126/scisignal.aao5749
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发表时间：
2018-02-06
影响因子：
7.3
通讯作者：
Rohatgi R
中科院分区：
文献类型：
--
作者：
Pusapati GV;Kong JH;Patel BB;Gouti M;Sagner A;Sircar R;Luchetti G;Ingham PW;Briscoe J;Rohatgi R
形态原Sonic Hedgehog （SHH）在发育过程中以浓度依赖的方式指导细胞命运。SHH信号通过七螺旋跨膜蛋白Smoothened （SMO）在靶细胞的细胞膜上传递，SMO激活GLI转录因子家族，其机制在脊椎动物中尚不明确。利用crispr编辑的零等位基因和小分子抑制剂，我们系统地分析了SMO与三种参与SMO信号传导的蛋白之间的上位性相互作用：异源三聚体G蛋白亚基Gα s、G蛋白偶联受体激酶2 （GRK2）和Gα s偶联受体GPR161。我们的实验揭示了一种信号机制，可以改变靶细胞对SHH的敏感性，从而改变SHH剂量反应曲线的形状。在成纤维细胞和脊髓神经祖细胞中，GPR161的缺失（之前被认为是基底SHH信号的抑制剂）增加了靶细胞在整个SHH浓度范围内的敏感性。令人惊讶的是，被认为通过拮抗GPR161起作用的GRK2和被GPR161激活的Gαs，即使在缺乏GPR161的细胞中也会影响SHH信号。我们提出，靶细胞对Hedgehog （Hh）形态因子的敏感性，以及由此对基因表达和分化结果的影响，可以通过g蛋白偶联受体聚集在Gαs和蛋白激酶A上的信号来控制。
The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G-protein subunit GαS, G protein–coupled receptor kinase 2 (GRK2), and the GαS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Surprisingly, GRK2, thought to function by antagonizing GPR161, and Gαs, which is activated by GPR161, influenced SHH signaling even in cells lacking GPR161. We propose that the sensitivity of target cells to Hedgehog (Hh) morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G-protein coupled receptors that converge on Gαs and Protein Kinase A.
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影响因子：
5.3
作者：
Meloni, Alison R.;Fralish, Gregory B.;Caron, Marc G.
通讯作者：
Caron, Marc G.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
7.5
作者：
Homan, Kristoff T.;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
DOI：
10.1073/pnas.93.17.9067
发表时间：
1996-08-20
影响因子：
11.1
作者：
Bronson, SK;Plaehn, EG;Smithies, O
通讯作者：
Smithies, O
影响因子：
4
作者：
Cohen, Michael;Briscoe, James;Blassberg, Robert
通讯作者：
Blassberg, Robert