CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways
CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways
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DOI：
10.1124/mol.116.105502
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发表时间：
2016-10-01
影响因子：
3.6
通讯作者：
Sakmar, Thomas P.
中科院分区：
文献类型：
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作者：
Berchiche, Yamina A.;Sakmar, Thomas P.
G蛋白偶联受体（GPCR）C-X-C趋化因子受体3（CXCR 3）是一种潜在的药物靶点，介导与癌症转移和炎症性疾病相关的信号传导。CXCR 3初级转录物具有三种潜在的可变剪接变体，并且细胞类型特异性表达导致被认为具有不同功能特征的受体变体。然而，配体结合CXCR 3选择性剪接变异体及其下游信号传导途径的分子药理学研究仍然很少。为了更好地理解CXCR 3选择性剪接的功能后果的作用，我们测量了响应于四种不同的趋化因子配体（CXCL 4、CXCL 9、CXCL 10和CXCL 11）的信号传导，所述趋化因子配体在CXCR 3处具有激动剂活性。CXCL 10和CXCL 11均激活剪接变体CXCR 3A。CXCL 10对G α（i）活化和细胞外信号调节激酶（ERK）1/2磷酸化显示完全激动活性，对β-抑制蛋白募集显示部分激动活性，而CXCL 9仅触发适度的ERK 1/2磷酸化。CXCL 11诱导CXCR 3B介导的β-arrestin募集和很少的ERK磷酸化。CXCR 3Alt信号传导仅限于响应趋化因子CXCL 11、CXCL 10和CXCL 9的适度配体诱导的受体内化和ERK 1/2磷酸化。这些结果表明，CXCR 3剪接变体激活不同的信号传导途径，并且CXCR 3变体功能不是冗余的，表明组织特异性偏向激动的机制。我们的数据显示了趋化因子受体信号传导的另一层复杂性，可能被利用来靶向特定的CXCR 3剪接变体。
The G protein-coupled receptor (GPCR) C-X-C chemokine receptor 3 (CXCR3) is a potential drug target that mediates signaling involved in cancer metastasis and inflammatory diseases. The CXCR3 primary transcript has three potential alternative splice variants and cell-type specific expression results in receptor variants that are believed to have different functional characteristics. However, the molecular pharmacology of ligand binding to CXCR3 alternative splice variants and their downstream signaling pathways remain poorly explored. To better understand the role of the functional consequences of alternative splicing of CXCR3, we measured signaling in response to four different chemokine ligands (CXCL4, CXCL9, CXCL10, and CXCL11) with agonist activity at CXCR3. Both CXCL10 and CXCL11 activated splice variant CXCR3A. Whereas CXCL10 displayed full agonistic activity for G alpha(i) activation and extracellular signal regulated kinase ( ERK) 1/2 phosphorylation and partial agonist activity for beta-arrestin recruitment, CXCL9 triggered only modest ERK1/2 phosphorylation. CXCL11 induced CXCR3B-mediated beta-arrestin recruitment and little ERK phosphorylation. CXCR3Alt signaling was limited to modest ligand-induced receptor internalization and ERK1/2 phosphorylation in response to chemokines CXCL11, CXCL10, and CXCL9. These results show that CXCR3 splice variants activate different signaling pathways and that CXCR3 variant function is not redundant, suggesting a mechanism for tissue specific biased agonism. Our data show an additional layer of complexity for chemokine receptor signaling that might be exploited to target specific CXCR3 splice variants.