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MASTL 通过激酶非依赖的信号通路促进细胞收缩和运动。

MASTL promotes cell contractility and motility through kinase-independent signaling.

机构信息

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, and Center for Integrative Biological Signalling Studies, Freiburg, Germany.

出版信息

J Cell Biol. 2020 Jun 1;219(6). doi: 10.1083/jcb.201906204.

DOI:10.1083/jcb.201906204
PMID:32311005
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7265322/
Abstract

Microtubule-associated serine/threonine-protein kinase-like (MASTL) is a mitosis-accelerating kinase with emerging roles in cancer progression. However, possible cell cycle-independent mechanisms behind its oncogenicity remain ambiguous. Here, we identify MASTL as an activator of cell contractility and MRTF-A/SRF (myocardin-related transcription factor A/serum response factor) signaling. Depletion of MASTL increased cell spreading while reducing contractile actin stress fibers in normal and breast cancer cells and strongly impairing breast cancer cell motility and invasion. Transcriptome and proteome profiling revealed MASTL-regulated genes implicated in cell movement and actomyosin contraction, including Rho guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and MRTF-A target genes tropomyosin 4.2 (TPM4), vinculin (VCL), and nonmuscle myosin IIB (NM-2B, MYH10). Mechanistically, MASTL associated with MRTF-A and increased its nuclear retention and transcriptional activity. Importantly, MASTL kinase activity was not required for regulation of cell spreading or MRTF-A/SRF transcriptional activity. Taken together, we present a previously unknown kinase-independent role for MASTL as a regulator of cell adhesion, contractility, and MRTF-A/SRF activity.

摘要

微管相关丝氨酸/苏氨酸蛋白激酶样（MASTL）是一种有丝分裂加速激酶，在癌症进展中具有新兴作用。然而，其致癌性背后可能存在细胞周期非依赖性机制仍不清楚。在这里，我们发现 MASTL 是细胞收缩性和 MRTF-A/SRF（肌球蛋白相关转录因子 A/血清反应因子）信号的激活剂。MASTL 的耗竭增加了细胞铺展，同时减少了正常和乳腺癌细胞中的收缩性肌动蛋白应力纤维，并强烈损害了乳腺癌细胞的迁移和侵袭能力。转录组和蛋白质组谱分析揭示了 MASTL 调节的与细胞运动和肌动球蛋白收缩相关的基因，包括 Rho 鸟嘌呤核苷酸交换因子 2（GEF-H1，ARHGEF2）和 MRTF-A 靶基因原肌球蛋白 4.2（TPM4）、纽蛋白（VCL）和非肌肉肌球蛋白 IIB（NM-2B，MYH10）。在机制上，MASTL 与 MRTF-A 结合并增加其核保留和转录活性。重要的是，MASTL 激酶活性对于调节细胞铺展或 MRTF-A/SRF 转录活性不是必需的。总之，我们提出了一个以前未知的 MASTL 作为细胞黏附、收缩性和 MRTF-A/SRF 活性调节剂的激酶非依赖性作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/9d8ac079eb66/JCB_201906204_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/8a0c1dfab2d7/JCB_201906204_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/9ab555ddf536/JCB_201906204_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/f3325636bb82/JCB_201906204_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/917f678269dd/JCB_201906204_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/4e94803fddf8/JCB_201906204_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/150172ab6dce/JCB_201906204_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/8c33b5f1cb11/JCB_201906204_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/e5c2ba23e5c8/JCB_201906204_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/eb8b420a1197/JCB_201906204_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/fada9c8913d4/JCB_201906204_Fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/aa2d031f8399/JCB_201906204_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/7e22aba46fb7/JCB_201906204_Fig9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/9d8ac079eb66/JCB_201906204_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/8a0c1dfab2d7/JCB_201906204_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/9ab555ddf536/JCB_201906204_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/f3325636bb82/JCB_201906204_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/917f678269dd/JCB_201906204_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/4e94803fddf8/JCB_201906204_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/150172ab6dce/JCB_201906204_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/8c33b5f1cb11/JCB_201906204_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/e5c2ba23e5c8/JCB_201906204_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/eb8b420a1197/JCB_201906204_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/fada9c8913d4/JCB_201906204_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/f3aedcdd546c/JCB_201906204_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/aa2d031f8399/JCB_201906204_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/7e22aba46fb7/JCB_201906204_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/e1db14cfcfff/JCB_201906204_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/7265322/9d8ac079eb66/JCB_201906204_FigS3.jpg

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