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首页> 外文期刊>Molecular and Cellular Biology >Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2
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Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2

机译：G蛋白偶联受体激酶2促进平滑的信号转导

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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 β-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by β-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 β-arrestin 2 and Smoothened.
机译：声波刺猬信号通路的失调与越来越多的人类癌症有关。在此途径中，平滑化的七跨膜（7TM）信号蛋白通过激活转录因子Gli来调节细胞增殖和分化。哺乳动物“平滑化”的活动通过与“平滑化”抑制剂Patched的相互作用而受三种不同的刺猬蛋白（印度，沙漠和音速刺猬）的控制。但是，对“平滑化”信号转导的机制了解甚少。我们表明，通过许多“常规” 7TM G蛋白偶联受体，G蛋白偶联受体激酶2（GRK2）调节信号传导的激酶参与了平滑信号传导。 GRK2的表达，而不是非催化失活的GRK2，与平滑化的活性协同表达Gli依赖性转录。此外，通过短发夹RNA（shRNA）敲除内源性GRK2可以显着降低响应平滑化激动剂SAG的信号传导，还可以抑制致癌的平滑化突变体Smo M2诱导的信号传导。我们发现，GRK2促进了活动的Smoothened和β-arrestin2之间的关联。的确，由shRNA抑制的β-arrestin2降低了由Smoothi和GRK2共表达介导的Gli依赖性信号传导。总之，这些数据表明，GRK2至少在一定程度上通过促进β-arrestin2与Smoothened之间的缔合在Smoothed信号传导中发挥了积极作用。

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