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首页> 外文期刊>Biochemistry >G Protein-Coupled Receptor Kinase 5 Phosphorylation of Hip Regulates Internalization of the Chemokine Receptor CXCR4
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G Protein-Coupled Receptor Kinase 5 Phosphorylation of Hip Regulates Internalization of the Chemokine Receptor CXCR4

机译：G蛋白偶联的受体激酶5的髋关节磷酸化调节趋化因子受体CXCR4的内在化。

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摘要

Regulation of the magnitude, duration, and localization of G proteincoupled receptor (GPCR) signaling responses is controlled by desensitization, internalization, and downregulation of the activated receptor. Desensitization is initiated by the phosphorylation of the activated receptor by GPCR kinases (GRKs) and the binding of the adaptor protein arrestin. In addition to phosphorylating activated GPCRs, GRKs have been shown to phosphorylate a variety of additional substrates. An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303?319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells. While Hip was previously implicated in chemokine receptor trafficking, we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4. Taken together, Hip has been identified as a novel substrate of GRK5 in vitro and in cells, and phosphorylation of Hip by GRK5 plays a role in modulating CXCR4 internalization.
机译：G蛋白偶联受体（GPCR）信号反应的幅度，持续时间和定位的调节受激活受体的脱敏，内在化和下调控制。脱敏作用是通过GPCR激酶（GRKs）激活的受体的磷酸化和衔接蛋白抑制蛋白的结合而引发的。除了磷酸化激活的GPCR外，GRKs还被证明可以磷酸化多种其他底物。新型GRK底物的体外筛选显示Hsp70相互作用蛋白（Hip）作为底物。 GRK5而非GRK2在体外与Hip结合并化学计量磷酸化了Hip。 GRK5的主要结合域定位到Hip的303-319残基上，而磷酸化的主要位点被确定为Ser-346。 GRK5还与细胞中Ser-346上的Hip结合并使其磷酸化。虽然Hip以前与趋化因子受体的转运有关，但我们发现Ser-346的磷酸化是激动剂诱导的趋化因子受体CXCR4内在化所必需的。两者合计，已被确定为Hip在体外和细胞中是GRK5的新型底物，并且GRK5对Hip的磷酸化在调节CXCR4内在化中起作用。

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