Cleavage of tropomodulin-3 by asparagine endopeptidase promotes cancer malignancy by actin remodeling and SND1/RhoA signaling.
Cleavage of tropomodulin-3 by asparagine endopeptidase promotes cancer malignancy by actin remodeling and SND1/RhoA signaling.
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天冬酰胺内肽酶裂解原调节蛋白 3 通过肌动蛋白重塑和 SND1/RhoA 信号传导促进癌症恶性
DOI：
10.1186/s13046-022-02411-4
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发表时间：
2022-06-28
影响因子：
11.3
通讯作者：
Lin, Yingying
中科院分区：
文献类型：
--
作者：
Chen, Binghong;Wang, Mengying;Qiu, Junjun;Liao, Keman;Zhang, Wenrui;Lv, Qi;Ma, Chunhui;Qian, Zhongrun;Shi, Zhonggang;Liang, Rong;Lin, Yan;Ye, Jiazhou;Qiu, Yongming;Lin, Yingying
背景细胞的异常增殖和迁移是肿瘤发生和恶性的标志。天冬酰胺内肽酶（AEP）具有特异性底物切割能力，在多种癌症中发挥促癌作用。然而，AEP在肿瘤增殖和迁移中的潜在机制仍不清楚。Western blotting检测蛋白表达。采用单细胞/核基因测序技术检测Tmod 3在肿瘤组织中的异质性表达。CCK-8测定、流式细胞术测定、集落形成测定、Transwell测定和划痕愈合测定作为细胞功能实验。小鼠颅内异种移植瘤进行了研究，在体内experiments.ResultsHere，我们表明，AEP切割无处不在的细胞骨架调节蛋白，troommodulin-3（Tmod 3）在天冬酰胺157（N157），并产生两个功能截断（tTmod 3-N和tTmod 3-C）。在多种肿瘤中检测到截短的Tmod 3，并发现其与高级别胶质瘤的不良预后相关。功能研究表明，tTmod 3-N和tTmod 3-C分别增强癌细胞迁移和增殖。动物模型进一步揭示了AEP截短的Tmod 3在体内的促肿瘤作用。从机制上讲，tTmod 3-N富集在细胞皮质中，并竞争性抑制野生型Tmod 3对丝状肌动蛋白（F-肌动蛋白）的尖端加帽作用，导致肌动蛋白重塑。结论新发现的AEP-Tmod 3蛋白酶信号轴是一种新的肿瘤细胞增殖和迁移的“双重调节”机制。我们的工作为癌症增殖和侵袭性进展的潜在机制提供了新的线索，并为靶向AEP或Tmod 3进行治疗提供了证据。
BackgroundAbnormal proliferation and migration of cells are hallmarks of cancer initiation and malignancy. Asparagine endopeptidase (AEP) has specific substrate cleavage ability and plays a pro-cancer role in a variety of cancers. However, the underlying mechanism of AEP in cancer proliferation and migration still remains unclear.MethodsCo-immunoprecipitation and following mass spectrometry were used to identify the substrate of AEP. Western blotting was applied to measure the expression of proteins. Single cell/nuclear-sequences were done to detect the heterogeneous expression of Tmod3 in tumor tissues. CCK-8 assay, flow cytometry assays, colony formation assay, Transwell assay and scratch wound-healing assay were performed as cellular functional experiments. Mouse intracranial xenograft tumors were studied in in vivo experiments.ResultsHere we showed that AEP cleaved a ubiquitous cytoskeleton regulatory protein, tropomodulin-3 (Tmod3) at asparagine 157 (N157) and produced two functional truncations (tTmod3-N and tTmod3-C). Truncated Tmod3 was detected in diverse tumors and was found to be associated with poor prognosis of high-grade glioma. Functional studies showed that tTmod3-N and tTmod3-C enhanced cancer cell migration and proliferation, respectively. Animal models further revealed the tumor-promoting effects of AEP truncated Tmod3 in vivo. Mechanistically, tTmod3-N was enriched in the cell cortex and competitively inhibited the pointed-end capping effect of wild-type Tmod3 on filamentous actin (F-actin), leading to actin remodeling. tTmod3-C translocated to the nucleus, where it interacted with Staphylococcal Nuclease And Tudor Domain Containing 1 (SND1), facilitating the transcription of Ras Homolog Family Member A/Cyclin Dependent Kinases (RhoA/CDKs).ConclusionThe newly identified AEP-Tmod3 protease signaling axis is a novel “dual-regulation” mechanism of tumor cell proliferation and migration. Our work provides new clues to the underlying mechanisms of cancer proliferation and invasive progression and evidence for targeting AEP or Tmod3 for therapy.
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影响因子：
9.2
作者：
Ebrahim, Seham;Fujita, Tomoki;Millis, Bryan A.;Kozin, Elliott;Ma, Xuefei;Kawamoto, Sachiyo;Baird, Michelle A.;Davidson, Michael;Yonemura, Shigenobu;Hisa, Yasuo;Conti, Mary Anne;Adelstein, Robert S.;Sakaguchi, Hirofumi;Kachar, Bechara
通讯作者：
Kachar, Bechara
TRAF6 天冬酰胺酰内肽酶泛素化在肿瘤侵袭和转移中的功能作用
影响因子：
10.3
作者：
Lin, Yingying;Qiu, Yongming;Guo, Fang
通讯作者：
Guo, Fang
影响因子：
19
作者：
Goel S;DeCristo MJ;McAllister SS;Zhao JJ
通讯作者：
Zhao JJ
影响因子：
4
作者：
Cui Y;Li Q;Li H;Wang Y;Wang H;Chen W;Zhang S;Cao J;Liu T
通讯作者：
Liu T
影响因子：
2.7
作者：
Colpan M;Moroz NA;Kostyukova AS
通讯作者：
Kostyukova AS