Control of PKA stability and signalling by the RING ligase praja2
Control of PKA stability and signalling by the RING ligase praja2
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DOI：
10.1038/ncb2209
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发表时间：
2011-04-01
影响因子：
21.3
通讯作者：
Feliciello, Antonio
中科院分区：
文献类型：
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作者：
Lignitto, Luca;Carlucci, Annalisa;Feliciello, Antonio
g蛋白偶联受体（gpcr）的激活激活了环AMP的区隔化脉冲。cAMP的主要细胞效应物是蛋白激酶A (PKA)，它是一种由两个调节(R)和两个催化（PKAc）亚基组成的无活性全酶。与R亚基结合的cAMP解离全酶并释放催化部分，从而磷酸化一系列细胞蛋白。ppkac和R分量的重新结合终止了信号。在这里，我们报道了环连接酶praja2控制哺乳动物R亚基的稳定性。Praja2与PKA形成稳定的复合物，并被PKA磷酸化。升高的cAMP水平促进praja2介导的泛素化和随后的区隔化R亚基的蛋白水解，导致被激活的激酶持续的底物磷酸化。Praja2是有效的核cAMP信号传导和pka介导的长期记忆所必需的。因此，praja2调节R亚基的总浓度，调节cAMP对PKA信号输出的强度和持续时间。
Activation of G-protein-coupled receptors (GPCRs) mobilizes compartmentalized pulses of cyclic AMP. The main cellular effector of cAMP is protein kinase A (PKA), which is assembled as an inactive holoenzyme consisting of two regulatory (R) and two catalytic (PKAc) subunits. cAMP binding to R subunits dissociates the holoenzyme and releases the catalytic moiety, which phosphorylates a wide array of cellular proteins. Reassociation of PKAc and R components terminates the signal. Here we report that the RING ligase praja2 controls the stability of mammalian R subunits. Praja2 forms a stable complex with, and is phosphorylated by, PKA. Rising cAMP levels promote praja2-mediated ubiquitylation and subsequent proteolysis of compartmentalized R subunits, leading to sustained substrate phosphorylation by the activated kinase. Praja2 is required for efficient nuclear cAMP signalling and for PKA-mediated long-term memory. Thus, praja2 regulates the total concentration of R subunits, tuning the strength and duration of PKA signal output in response to cAMP.