Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors.
Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors.
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DOI：
10.1371/journal.pone.0069473
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Marra G
中科院分区：
文献类型：
--
作者：
Tiwari A;Schneider M;Fiorino A;Haider R;Okoniewski MJ;Roschitzki B;Uzozie A;Menigatti M;Jiricny J;Marra G
我们以前报道过KIAA 1199在人结直肠肿瘤（良性和恶性）中的表达明显高于正常结肠粘膜。在这项研究中，我们研究了该基因编码的蛋白质的功能，这是迄今为止未知的。免疫染色研究被用来揭示其亚细胞定位，蛋白质组学和基因表达实验进行鉴定可能与KIAA 1199和分子途径，它可能发挥作用的蛋白质。使用结肠癌细胞系，我们表明内源性和异位表达的KIAA 1199都分泌到细胞外环境中。在细胞内，主要分布于核周间隙（可能是内质网）和细胞膜。这两个细胞区室也过度代表在列表中的蛋白质鉴定的质谱作为推定的KIAA 1199相互作用和/或蛋白质编码的基因，其转录显着改变KIAA 1199表达。这些蛋白质组学和转录组学数据集一致地将KIAA 1199与几种基因/蛋白质和分子途径联系起来，包括ER过程，如蛋白质结合、转运和折叠;以及Ca 2+、G蛋白、肝配蛋白和Wnt信号传导。免疫沉淀实验证实了KIAA 1199与细胞膜受体ephrin A2和ER受体ITPR 3（Ca 2+信号传导的关键参与者）的相互作用。通过调节Ca 2+信号，KIAA 1199可以影响Wnt网络的不同分支。我们的研究结果表明，它可能负调控Wnt/CTNNB 1信号，其表达与细胞增殖和侵袭力下降有关。
We previously reported that the expression of KIAA1199 in human colorectal tumors (benign and malignant) is markedly higher than that in the normal colonic mucosa. In this study, we investigated the functions of the protein encoded by this gene, which are thus far unknown. Immunostaining studies were used to reveal its subcellular localization, and proteomic and gene expression experiments were conducted to identify proteins that might interact with KIAA1199 and molecular pathways in which it might play roles. Using colon cancer cell lines, we showed that both endogenous and ectopically expressed KIAA1199 is secreted into the extracellular environment. In the cells, it was found mainly in the perinuclear space (probably the ER) and cell membrane. Both cellular compartments were also over-represented in lists of proteins identified by mass spectrometry as putative KIAA1199 interactors and/or proteins encoded by genes whose transcription was significantly changed by KIAA1199 expression. These proteomic and transcriptomic datasets concordantly link KIAA1199 to several genes/proteins and molecular pathways, including ER processes like protein binding, transport, and folding; and Ca2+, G-protein, ephrin, and Wnt signaling. Immunoprecipitation experiments confirmed KIAA1199’s interaction with the cell-membrane receptor ephrin A2 and with the ER receptor ITPR3, a key player in Ca2+ signaling. By modulating Ca2+ signaling, KIAA1199 could affect different branches of the Wnt network. Our findings suggest it may negatively regulate the Wnt/CTNNB1 signaling, and its expression is associated with decreased cell proliferation and invasiveness.
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通讯作者：
Marra, Giancarlo