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NDR2 激酶有助于肺癌细胞中 RASSF1A 抑癌基因失活诱导的细胞侵袭和胞质分裂缺陷。

NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells.

机构信息

Normandie University, UNICAEN, UMR 1086 INSERM, F-14032, Caen, France.

Normandie University, UNICAEN, UPRES-EA-2608, F-14032, Caen, France.

出版信息

J Exp Clin Cancer Res. 2019 Apr 12;38(1):158. doi: 10.1186/s13046-019-1145-8.

DOI:10.1186/s13046-019-1145-8
PMID:30979377
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6461807/
Abstract

BACKGROUND

RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown.

METHODS

NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID-/- Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC).

RESULTS

We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC.

CONCLUSION

To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects.

摘要

背景

RASSF1A 是一种肿瘤抑制基因，在肺癌中经常失活，导致 YAP 依赖性上皮-间充质转化（EMT）。这种效应部分是由于 RhoB GTP 酶的抗迁移作用被抑制，通过 RhoB 的 GDP/GTP 交换因子 GEF-H1 的抑制性磷酸化而导致的。然而，在 RASSF1A 耗竭细胞中负责 RhoB/GEF-H1 失活的激酶仍然未知。

方法

通过 siRNA 或 shRNA 敲低 NDR1/2，研究其对人支气管上皮细胞（HBEC）中 RASSF1A 缺失时上皮-间充质转化、侵袭、异种移植形成和生长、细胞凋亡、增殖、胞质分裂、YAP/TAZ 激活的影响。

结果

我们在这里证明，YAP 激酶 NDR1/2 的耗竭可逆转 HBEC 中 RASSF1A 缺失时的迁移和转移特性。我们表明，NDR2 与 GEF-H1 直接相互作用（其中包含 NDR 磷酸化的共有基序 HXRXXS/T），导致 GEF-H1 磷酸化。我们进一步报告，RASSF1A/NDR2/GEF-H1/RhoB/YAP 轴参与人支气管细胞中的正常胞质分裂，因为在 HBEC 中，RASSF1A 或 GEF-H1 缺失时，染色体的正确分离是依赖于 NDR 的。

结论

总之，我们的数据支持这样一种模型，即在 RASSF1A 沉默后，NDR2 被激活，磷酸化并失活 GEF-H1，导致 RhoB 失活。这种由支气管细胞中 RASSF1A 缺失引起的级联反应是导致转移特性、YAP 激活和胞质分裂缺陷的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/475aa22f146d/13046_2019_1145_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/daa400c52c80/13046_2019_1145_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/ad0b7436cfe4/13046_2019_1145_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/3a3495b8f4ff/13046_2019_1145_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/be2ea53523cb/13046_2019_1145_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/a4f679239eaf/13046_2019_1145_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/49e867a16819/13046_2019_1145_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/6f3571913816/13046_2019_1145_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/475aa22f146d/13046_2019_1145_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/daa400c52c80/13046_2019_1145_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/ad0b7436cfe4/13046_2019_1145_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/3a3495b8f4ff/13046_2019_1145_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/be2ea53523cb/13046_2019_1145_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/a4f679239eaf/13046_2019_1145_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/49e867a16819/13046_2019_1145_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/6f3571913816/13046_2019_1145_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bd/6461807/475aa22f146d/13046_2019_1145_Fig8_HTML.jpg

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