Microtubule detyrosination drives symmetry breaking to polarize cells for directed cell migration.
Microtubule detyrosination drives symmetry breaking to polarize cells for directed cell migration.
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DOI：
10.1073/pnas.2300322120
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发表时间：
2023-05-30
影响因子：
11.1
通讯作者：
Barisic, Marin
中科院分区：
文献类型：
--
作者：
Lavrsen, Kirstine;Rajendraprasad, Girish;Leda, Marcin;Eibes, Susana;Vitiello, Elisa;Katopodis, Vasileios;Goryachev, Andrew B.;Barisic, Marin
参与细胞极性建立/维持的分子和细胞器的基于微管（MT）的转运对于定向细胞迁移至关重要。在这里，我们发现MT去酪氨酸引导基于驱动蛋白-1的腺瘤性结肠息肉病向皮质部位的运输，从而能够产生一个反馈回路，将MT动力学和基于驱动蛋白-1的运输联系起来。这对于定向细胞迁移所需的对称性破缺至关重要。失调的MT脱酪氨酸与癌症、神经变性和心力衰竭有关。最突出的脱酪氨酸相关缺陷，如受干扰的神经元迁移和癌症相关的EMT和血管生成，取决于细胞极化和定向迁移。因此，MT脱酪氨酸对细胞极性和定向迁移的影响可能在神经退行性疾病、癌症和心脏病中起重要作用。为了启动定向运动，细胞必须极化，建立一个扩张的前缘和一个收缩的后缘。这一破坏过程涉及细胞骨架的重组和调节分子的不对称分布。然而，在细胞迁移过程中，是什么触发并维持这种不对称性在很大程度上仍然难以捉摸。在这里，我们建立了一个基于微图案的一维运动分析，研究定向细胞迁移所需的对称性破缺的分子基础。我们发现微管（MT）去酪氨酸通过将基于驱动蛋白1的腺瘤性结肠息肉病（APC）蛋白运输到皮质部位来驱动细胞极化。这对于在1D和3D细胞迁移期间形成细胞的前缘至关重要。这些数据，结合生物物理模型，揭示了MT去酪氨酸在产生一个正反馈回路连接MT动力学和驱动蛋白-1为基础的运输的关键作用。因此，细胞极化过程中的对称性破坏依赖于由MT脱酪氨酸驱动的反馈回路，该反馈回路支持定向细胞迁移。
Microtubule (MT)-based transport of molecules and organelles involved in the establishment/maintenance of cell polarity is critical for directed cell migration. Here, we show that MT detyrosination guides kinesin-1-based transport of adenomatous polyposis coli towards the cortical sites, thereby enabling the generation of a feedback loop that links MT dynamics and kinesin-1-based transport. This is critical for the symmetry breaking required for directional cell migration. Dysregulated MT detyrosination has been associated with cancer, neurodegeneration, and heart failure. The most prominent detyrosination-related defects, like perturbed neuronal migration and cancer-associated EMT and angiogenesis, depend on cell polarization and directed migration. Thus, the impact of MT detyrosination on cell polarity and directed migration may play an important role in neurodegeneration, cancer, and heart diseases. To initiate directed movement, cells must become polarized, establishing a protrusive leading edge and a contractile trailing edge. This symmetry-breaking process involves reorganization of cytoskeleton and asymmetric distribution of regulatory molecules. However, what triggers and maintains this asymmetry during cell migration remains largely elusive. Here, we established a micropatterning-based 1D motility assay to investigate the molecular basis of symmetry breaking required for directed cell migration. We show that microtubule (MT) detyrosination drives cell polarization by directing kinesin-1-based transport of the adenomatous polyposis coli (APC) protein to cortical sites. This is essential for the formation of cell's leading edge during 1D and 3D cell migration. These data, combined with biophysical modeling, unveil a key role for MT detyrosination in the generation of a positive feedback loop linking MT dynamics and kinesin-1-based transport. Thus, symmetry breaking during cell polarization relies on a feedback loop driven by MT detyrosination that supports directed cell migration.
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影响因子：
64.5
作者：
Fukata, M;Watanabe, T;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
56.9
作者：
Aillaud, Chrystelle;Bosc, Christophe;Moutin, Marie-Jo
通讯作者：
Moutin, Marie-Jo
影响因子：
11.8
作者：
Chen J;Kholina E;Szyk A;Fedorov VA;Kovalenko I;Gudimchuk N;Roll-Mecak A
通讯作者：
Roll-Mecak A
DOI：
10.1083/jcb.200810041
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Doyle AD;Wang FW;Matsumoto K;Yamada KM
通讯作者：
Yamada KM
影响因子：
11.8
作者：
Aher A;Kok M;Sharma A;Rai A;Olieric N;Rodriguez-Garcia R;Katrukha EA;Weinert T;Olieric V;Kapitein LC;Steinmetz MO;Dogterom M;Akhmanova A
通讯作者：
Akhmanova A