Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.
Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.
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DOI：
10.1126/scisignal.2001707
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发表时间：
2011-08-09
影响因子：
7.3
通讯作者：
Lefkowitz RJ
中科院分区：
文献类型：
--
作者：
Nobles KN;Xiao K;Ahn S;Shukla AK;Lam CM;Rajagopal S;Strachan RT;Huang TY;Bressler EA;Hara MR;Shenoy SK;Gygi SP;Lefkowitz RJ
G蛋白偶联受体（GPCR，也称为七跨膜受体）通过GPCR激酶（GRKs）的磷酸化通过促进受体与β-抑制蛋白的相互作用在受体功能调节中起重要作用。这些多功能衔接蛋白通过减少受体与G蛋白的偶联并促进受体内化来使GPCR脱敏，并通过β-抑制蛋白特异性途径介导GPCR信号传导。详细定位单个GRK靶向的GPCR上的磷酸化位点，并了解这些位点如何调节β-抑制蛋白结合的特定功能后果，可能有助于发现靶向单个β-抑制蛋白功能的治疗药物。β2-肾上腺素能受体（β 2-adrenergic receptor，β2AR）的羧基末端和胞内环有许多丝氨酸和苏氨酸残基，是潜在的磷酸化位点。我们监测了β2AR在特定位点的磷酸化，当用激动剂刺激时，该激动剂通过G蛋白介导的和β-抑制蛋白介导的途径促进信号传导，或者用偏向性配体刺激时，该偏向性配体在存在完整的GRK补体的情况下或当GRK 2或GRK 6耗尽时仅通过β-抑制蛋白介导的事件促进信号传导。我们将单个GRK的受体磷酸化的特定和不同模式与β-arrestins的功能相关联，并提出不同GRK建立的不同磷酸化模式建立了一个“条形码”，该条形码赋予招募的β-arrestin不同的构象，从而调节其功能活性。
Phosphorylation of G protein–coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arrestins. These multifunctional adaptor proteins desensitize GPCRs, by reducing receptor coupling to G proteins and facilitating receptor internalization, and mediate GPCR signaling through β-arrestin–specific pathways. Detailed mapping of the phosphorylation sites on GPCRs targeted by individual GRKs and an understanding of how these sites regulate the specific functional consequences of β-arrestin engagement may aid in the discovery of therapeutic agents targeting individual β-arrestin functions. The β2-adrenergic receptor (β2AR) has many serine and threonine residues in the carboxyl-terminal tail and the intracellular loops, which are potential sites of phosphorylation. We monitored the phosphorylation of the β2AR at specific sites upon stimulation with an agonist that promotes signaling by both G protein–mediated and β-arrestin–mediated pathways or with a biased ligand that promotes signaling only through β-arrestin–mediated events in the presence of the full complement of GRKs or when either GRK2 or GRK6 was depleted. We correlated the specific and distinct patterns of receptor phosphorylation by individual GRKs with the functions of β-arrestins and propose that the distinct phosphorylation patterns established by different GRKs establish a “barcode” that imparts distinct conformations to the recruited β-arrestin, thus regulating its functional activities.
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影响因子：
4.4
作者：
Bakalarski, Corey E.;Elias, Joshua E.;Villen, Judit;Haas, Wilhelm;Gerber, Scott A.;Everley, Patrick A.;Gygi, Steven P.
通讯作者：
Gygi, Steven P.
DOI：
10.1073/pnas.0804745105
发表时间：
2008-09-23
影响因子：
11.1
作者：
Kim, Il-Man;Tilley, Douglas G.;Rockman, Howard A.
通讯作者：
Rockman, Howard A.
影响因子：
7.7
作者：
Charest, PG;Terrillon, S;Bouvier, M
通讯作者：
Bouvier, M
影响因子：
4.8
作者：
Seibold, A;January, BG;Clark, RB
通讯作者：
Clark, RB
影响因子：
4.8
作者：
Krasel, Cornelius;Zabel, Ulrike;Lohse, Martin J.
通讯作者：
Lohse, Martin J.