GGA2 interacts with EGFR cytoplasmic domain to stabilize the receptor expression and promote cell growth.
GGA2 interacts with EGFR cytoplasmic domain to stabilize the receptor expression and promote cell growth.
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GGA2与EGFR细胞质结构域相互作用，以稳定受体表达并促进细胞生长。
DOI：
10.1038/s41598-018-19542-4
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发表时间：
2018-01-22
影响因子：
4.6
通讯作者：
Waguri S
中科院分区：
文献类型：
--
作者：
Uemura T;Kametaka S;Waguri S
表皮生长因子受体（EGFR）信号转导及其在配体结合后的下调已被广泛记录。然而，细胞维持稳态EGFR表达的机制仍然知之甚少。在这里，我们报告了一个新的高尔基体定位，γ-adaptin耳，ADP核糖基化因子结合蛋白2（GGA 2）在EGFR营业额的控制作用。而GGA 1或GGA 3消耗增加EGFR表达，GGA 2消耗RNAi大大降低了EGFR的稳态表达，反映了EGFR的溶酶体降解增强。随后的pull-down分析显示来自三种GGA的VHS-GAT结构域与EGFR的胞质质膜区（jxt）的相互作用，其依赖于VHS结构域中的N108。邻位连接法也显示了GGA 2和EGFR之间的原位稳态相互作用。此外，在GGA 2耗尽的细胞中EGFR表达的降低通过额外的GGA 1或GGA 3耗尽而逆转，表明GGA 1和GGA 3促进EGFR降解。此外，在细胞培养和异种移植实验中，GGA 2耗尽的细胞具有降低的EGF信号传导和细胞增殖。最后，GGA 2在30.8%的人肝细胞癌和23.3%的结直肠癌中上调。总之，这些结果表明GGA 2通过与EGFR相互作用以维持受体表达来支持细胞生长。
Epidermal growth factor receptor (EGFR) signaling and its downregulation upon ligand binding have been extensively documented. However, the mechanisms by which cells maintain steady-state EGFR expression remain poorly understood. Here, we report a novel role of Golgi-localized, γ-adaptin ear-containing, ADP ribosylation factor-binding protein 2 (GGA2) in the control of EGFR turnover. Whereas GGA1- or GGA3-depletion increased EGFR expression, GGA2-depletion by RNAi greatly reduced steady-state expression of EGFR, reflecting enhanced lysosomal degradation of EGFR. Subsequent pull-down assays showed interactions of VHS-GAT domains from three GGAs with the cytoplasmic juxtamembrane region (jxt) of EGFR, which was dependent on N108 in the VHS domain. Proximity ligation assay also revealed the steady-state interaction between GGA2 and EGFR in situ. Moreover, reduced expression of EGFR in GGA2-depleted cells was reversed by additional depletion of GGA1 or GGA3, suggesting that GGA1 and GGA3 promote EGFR degradation. In addition, GGA2-depleted cells had reduced EGF signaling and cell proliferation in cell culture and xenograft experiments. Finally, GGA2 was upregulated in 30.8% of human hepatocellular carcinomas and 23.3% of colorectal cancers. Together, these results indicate that GGA2 supports cell growth by interacting with EGFR for sustaining the receptor expression.
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影响因子：
8
作者：
Lin, YM;Furukawa, Y;Nakamura, Y
通讯作者：
Nakamura, Y
影响因子：
8.4
作者：
McKay, JA;Murray, LJ;McLeod, HL
通讯作者：
McLeod, HL
影响因子：
3.3
作者：
Chen, X;Cheung, ST;Brown, PO
通讯作者：
Brown, PO
DOI：
10.1073/pnas.082235699
发表时间：
2002-06-11
影响因子：
11.1
作者：
Doray, B;Bruns, K;Kornfeld, SA
通讯作者：
Kornfeld, SA
影响因子：
6
作者：
Guerra F;Bucci C
通讯作者：
Bucci C