Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2
Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2
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DOI：
10.1128/mcb.00546-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Caron, Marc G.
中科院分区：
文献类型：
--
作者：
Meloni, Alison R.;Fralish, Gregory B.;Caron, Marc G.
Sonic hedgehog通路的失调与越来越多的人类癌症有关。在该途径中，七跨膜（7 TM）信号蛋白Smoothened通过激活转录因子Gli来调节细胞增殖和分化。哺乳动物Smoothened的活性由三种不同的刺猬蛋白（Indian hedgehog、Desert hedgehog和Sonic hedgehog）通过与Smoothened抑制剂Patched相互作用控制。然而，Smoothened的信号转导机制知之甚少。我们表明，激酶调节信号通过许多“传统的”7 TM G蛋白偶联受体，G蛋白偶联受体激酶2（GRK 2），参与Smoothened信号。GRK 2的表达，但不是催化失活GRK 2，与活性Smoothened协同介导Gli依赖性转录。此外，通过短发夹RNA（shRNA）敲低内源性GRK 2显著降低响应于Smoothened激动剂SAG的信号传导，并且还抑制由致癌Smoothened突变体Smo M2诱导的信号传导。我们发现GRK 2促进了活性Smoothened和β-arrestin 2之间的关联。事实上，通过Smoothened和GRK 2的共表达介导的Gli依赖性信号传导通过用shRNA敲低β-arrestin 2而减弱。总之，这些数据表明GRK 2在Smoothened信号传导中起着积极的作用，至少部分是通过促进P-arrestin 2和Smoothened之间的关联。
Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many "conventional" 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and beta-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by beta-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between P-arrestin 2 and Smoothened.