A long isoform of GIV/Girdin contains a PDZ-binding module that regulates localization and G-protein binding.
A long isoform of GIV/Girdin contains a PDZ-binding module that regulates localization and G-protein binding.
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DOI：
10.1016/j.jbc.2021.100493
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Ghosh P
中科院分区：
文献类型：
--
作者：
Ear J;Abd El-Hafeez AA;Roy S;Ngo T;Rajapakse N;Choi J;Khandelwal S;Ghassemian M;McCaffrey L;Kufareva I;Sahoo D;Ghosh P
PDZ 结构域是真核生物中最丰富的蛋白质结构域之一，经常出现在连接定位的支架蛋白上。各种信号分子通过 PDZ 结合基序 (PBM) 与 PDZ 蛋白结合，并微调细胞信号传导。然而，这种相互作用如何影响蛋白质功能很难预测，必须凭经验解决。在这里，我们描述了鸟嘌呤核苷酸交换因子 GIV/Girdin (CCDC88A) 的长亚型，我们将其命名为 GIV-L，它在从无脊椎动物到脊椎动物的整个进化过程中都是保守的，并且包含 PBM。与缺乏 PBM 且为胞质的 GIV 不同，GIV-L 定位于细胞连接处并具有 PDZ 相互作用组（如通过注释人类细胞图谱和 BioID 邻近标记研究所示），这会影响 GIV-L 通过其鸟嘌呤核苷酸交换调节器 (GEM) 模块结合和激活三聚体 G 蛋白 Gαi 的能力。这种 GEM 模块仅存在于脊椎动物中。我们认为，GIV 中的两个功能模块可能是按顺序进化的：通过 PBM 结合 PDZ 蛋白的能力在无脊椎动物中进化得较早，而 G 蛋白结合和激活可能仅在脊椎动物中进化得较晚。 Caco-2 细胞的表型研究表明，GIV 和 GIV-L 可能对细胞生长、增殖（细胞周期）和存活具有拮抗作用。人类结肠组织的免疫组织化学分析表明，在癌症发生期间，GIV 表达增加，同时 GIV-L 减少。总而言之，这些发现揭示了 GIV/CCDC88A 转录本的调节如何帮助实现蛋白质模块化，从而使蛋白质能够发挥相反的作用，既可以作为肿瘤抑制基因 (GIV-L)，也可以作为癌基因 (GIV)。
PDZ domains are one of the most abundant protein domains in eukaryotes and are frequently found on junction-localized scaffold proteins. Various signaling molecules bind to PDZ proteins via PDZ-binding motifs (PBM) and fine-tune cellular signaling. However, how such interaction affects protein function is difficult to predict and must be solved empirically. Here we describe a long isoform of the guanine nucleotide exchange factor GIV/Girdin (CCDC88A) that we named GIV-L, which is conserved throughout evolution, from invertebrates to vertebrates, and contains a PBM. Unlike GIV, which lacks PBM and is cytosolic, GIV-L localizes onto cell junctions and has a PDZ interactome (as shown through annotating Human Cell Map and BioID-proximity labeling studies), which impacts GIV-L's ability to bind and activate trimeric G-protein, Gαi, through its guanine-nucleotide exchange modulator (GEM) module. This GEM module is found exclusively in vertebrates. We propose that the two functional modules in GIV may have evolved sequentially: the ability to bind PDZ proteins via the PBM evolved earlier in invertebrates, whereas G-protein binding and activation may have evolved later only among vertebrates. Phenotypic studies in Caco-2 cells revealed that GIV and GIV-L may have antagonistic effects on cell growth, proliferation (cell cycle), and survival. Immunohistochemical analysis in human colon tissues showed that GIV expression increases with a concomitant decrease in GIV-L during cancer initiation. Taken together, these findings reveal how regulation in GIV/CCDC88A transcript helps to achieve protein modularity, which allows the protein to play opposing roles either as a tumor suppressor (GIV-L) or as an oncogene (GIV).
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