GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion
GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion
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DOI：
10.1038/sj.onc.1208395
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发表时间：
2005-03-03
期刊：
影响因子：
8
通讯作者：
Foehr, ED
中科院分区：
文献类型：
--
作者：
Shashidhar, S;Lorente, G;Foehr, ED
GPR 56（也称为TM 7 XN 1）是一种新发现的分泌素家族的孤儿G蛋白偶联受体（GPCR），在神经祖细胞的发育中发挥作用，并与人脑的发育畸形有关。GPR 56与其他促分泌素样家族成员不同，因为它具有非常大的N-末端胞外区（381个氨基酸），并且在这个新的亚类中包含新的特征，由四个半胱氨酸残基组成，其限定位于第一跨膜结构域之前的GPCR蛋白水解位点（GPS基序）。氨基末端结构域的其余部分含有大量类似于粘蛋白样蛋白的可能的N-和O-连接的糖基化位点。这些特征表明在细胞-细胞或细胞-基质相互作用中的作用。在这里，我们使用功能基因组学证明了多形性胶质母细胞瘤中GPR 56的上调。免疫组织化学研究证实了GPR 56蛋白在大多数胶质母细胞瘤/星形细胞瘤肿瘤样品中的表达，而在正常成人脑组织中的表达水平不可检测。使用抗GPR 56抗体对人脑胶质瘤细胞的免疫荧光分析表明，GPR 56表达于膜丝状伪足的前缘，并与α-辅肌动蛋白共定位。纯化的重组GPR 56胞外区蛋白抑制胶质瘤细胞粘附，并导致细胞骨架形态异常和细胞变圆。这些结果表明，胞外结构域可能竞争未鉴定的配体，并阻断GPR 56在细胞附着中的正常功能。在报告基因测定中，GPR 56的过表达激活NF-κ B、派-1和TCF转录应答元件。这些通路与细胞骨架信号传导、粘附和肿瘤生物学有关。上述结果表明，GPR 56作为粘附GPCR并参与粘附信号传导。
GPR56 ( also known as TM7XN1) is a newly discovered orphan G-protein-coupled receptor ( GPCR) of the secretin family that has a role in the development of neural progenitor cells and has been linked to developmental malformations of the human brain. GPR56 diverges from other secretin-like family members in that it has an extremely large N-terminal extracellular region (381 amino acids) and contains a novel feature among this new subclass, consisting of four cysteine residues that define a GPCR proteolytic site (GPS motif) located just before the first transmembrane spanning domain. The rest of the amino-terminal domain contains a large number of possible N- and O-linked glycosylation sites similar to mucin-like proteins. These features suggest a role in cell cell, or cell-matrix interactions. Here, we demonstrate upregulation of GPR56 in glioblastoma multiforme tumors using functional genomics. Immunohistochemistry studies confirmed the expression of GPR56 protein in a majority of glioblastoma/astrocytoma tumor samples with undetectable levels of expression in normal adult brain tissue. Immunofluorescence analysis of human glioma cells using anti-GPR56 antibodies demonstrate that GPR56 is expressed on the leading edge of membranefilopodia and colocalizes with alpha-actinin. Purified recombinant GPR56 extracellular domain protein inhibits glioma cell adhesion and causes abnormal cytoskeletal morphology and cell rounding. These results indicate that the extracellular domain may compete for unidentified ligand(s), and block the normal function of GPR56 in cell attachment. In reporter assays, overexpression of GPR56 activates the NF-kappaB, PAI-1 and TCF transcriptional response elements. These pathways have been implicated in cytoskeletal signaling, adhesion and tumor biology. The above results indicate that GPR56 serves as an adhesion GPCR and is involved in adhesion signaling.