Phosphorylation of MICAL2 by ARG promotes head and neck cancer tumorigenesis by regulating skeletal rearrangement
Phosphorylation of MICAL2 by ARG promotes head and neck cancer tumorigenesis by regulating skeletal rearrangement
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ARG 磷酸化 MICAL2 通过调节骨骼重排促进头颈癌肿瘤发生
DOI：
10.1038/s41388-021-02101-z
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发表时间：
2021-11
期刊：
影响因子：
8
通讯作者：
Jingtao Luo
中科院分区：
文献类型：
--
作者：
Ze Zhang;Ruoyan Liu;Yafei Wang;Yun Wang;Yanjie Shuai;Chuangwu Ke;Rui Jin;Xudong Wang;Jingtao Luo
肌动蛋白的细胞骨架结构为关键的细胞行为提供了结构基础。在癌细胞中，肌动蛋白细胞骨架的变化可能是增殖、侵袭和转移扩散的先决条件。然而，其潜在机制在很大程度上仍然未知。在这里，我们发现MICAL 2在头颈部鳞状细胞癌（HNSCC）中增加，与患者生存率呈负相关，促进HNSCC生长，侵袭和迁移。MICAL 2作为黄素蛋白单加氧酶，通过特异性氧化F-肌动蛋白的甲硫氨酸44和47残基直接诱导肌动蛋白丝解聚。激酶ARG与MICAL 2相互作用并增强MICAL 2介导的肌动蛋白分解。直接磷酸化测定和质谱法证实，ARG在Tyr 445、Tyr 463和Tyr 488处磷酸化MICAL 2。用苯丙氨酸取代纯化的重组MICAL 2-氧化还原的Tyr 445或Tyr 463残基（产生不可磷酸化的突变体）消除了由ARG诱导的增强的MICAL 2-介导的F-肌动蛋白分解。一致地，非磷酸化MICAL 2突变体（MICAL 2 Y 445 F和MICAL 2 Y 463 F，而不是MICAL 2 Y 488 F）的异位表达未能改善HNSCC细胞生长，而野生型MICAL 2或MICAL 2 Y 488 F的表达挽救了由MICAL 2敲低诱导的受损的增殖。此外，MICAL 2抑制剂CCG-1423显示出抑制HNSCC细胞增殖、侵袭和迁移。综上所述，我们的研究结果表明，通过ARG在Tyr 445和Tyr 463处磷酸化MICAL 2介导F-肌动蛋白分解并促进HNSCC进展。
The actin cytoskeletal architecture provides the structural underpinnings for crucial cellular behaviors. In cancer cells, changes in the actin cytoskeleton may serve as prerequisites for proliferation, invasion, and metastatic dissemination. However, the underlying mechanisms remain largely unknown. Here, we show that MICAL2, which is increased in head and neck squamous cell carcinoma (HNSCC) and inversely associated with patient survival, promotes HNSCC growth, invasion, and migration. MICAL2 serves as a flavoprotein monooxygenase and directly induces actin filament depolymerization by specifically oxidizing the methionine 44 and 47 residues of F-actin. The kinase ARG interacts with MICAL2 and augments MICAL2-mediated actin disassembly. Direct phosphorylation assay and mass spectrometry confirmed that ARG phosphorylates MICAL2 at Tyr445, Tyr463, and Tyr488. Substitution of the Tyr445 or Tyr463 residue of purified recombinant MICAL2-redox with phenylalanine (generating a non-phosphorylatable mutant) abolishes the enhanced MICAL2-mediated F-actin disassembly induced by ARG. Consistently, ectopic expression of non-phosphorylatable MICAL2 mutants (MICAL2Y445Fand MICAL2Y463F, not MICAL2Y488F) failed to ameliorate HNSCC cell growth, whereas expression of wild-type MICAL2 or MICAL2Y488Frescued the impaired proliferation induced by MICAL2 knockdown. Moreover, CCG-1423, an inhibitor of MICAL2, was shown to inhibit HNSCC cell proliferation, invasion, and migration. Taken together, our findings indicate that phosphorylation of MICAL2 at Tyr445 and Tyr463 by ARG mediates F-actin disassembly and promotes HNSCC progression.
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