期刊
CURRENT BIOLOGY
卷 24, 期 14, 页码 1628-1635出版社
CELL PRESS
DOI: 10.1016/j.cub.2014.05.069
关键词
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资金
- Human Frontier Science Program Young Investigator Grant [RGY 67/2008]
- Polish Ministry of Science and Higher Education [454/N-MPG/2009/0]
- European Research Council
- Medical Research Council UK
- Canadian Institutes for Health Research
- National Science and Engineering Research Council
- BBSRC [BB/F021402, BB/F019769]
- University Research Fellowship from the Royal Society
- Wellcome Trust grant [WT090233]
- Cancer Institute NSW
- Cure Cancer Australia Foundation [1070498]
- ECR grant from the Sydney Medical School
- UCL Comprehensive Biomedical Research Centre
- BBSRC [BB/F021402/1, BB/F019769/1] Funding Source: UKRI
- MRC [MC_UP_1205/1, MC_UU_12018/5] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F021402/1, BB/F019769/1] Funding Source: researchfish
- Medical Research Council [MC_UU_12018/5, MC_UP_1205/1] Funding Source: researchfish
- MRC Laboratory for Molecular Cell Biology (LMCB) [Paluch ERC Research Grant, HFSP Research Grant] Funding Source: researchfish
The contractile actin cortex is a thin layer of actin, myosin, and actin-binding proteins that subtends the membrane of animal cells. The cortex is the main determinant of cell shape and plays a fundamental role in cell division [1-3], migration [4], and tissue morphogenesis [5]. For example, cortex contractility plays a crucial role in amoeboid migration of metastatic cells [6] and during division, where its misregulation can lead to aneuploidy [7]. Despite its importance, our knowledge of the cortex is poor, and even the proteins nucleating it remain unknown, though a number of candidates have been proposed based on indirect evidence [8-15]. Here, we used two independent approaches to identify cortical actin nucleators: a proteomic analysis using cortex-rich isolated blebs, and a localization/small hairpin RNA (shRNA) screen searching for phenotypes with a weakened cortex or altered contractility. This unbiased study revealed that two proteins generated the majority of cortical actin: the formin mDia1 and the Arp2/3 complex. Each nucleator contributed a similar amount of F-actin to the cortex but had very different accumulation kinetics. Electron microscopy examination revealed that each nucleator affected cortical network architecture differently. mDia1 depletion led to failure in division, but Arp2/3 depletion did not. Interestingly, despite not affecting division on its own, Arp2/3 inhibition potentiated the effect of mDia1 depletion. Our findings indicate that the bulk of the actin cortex is nucleated by mDia1 and Arp2/3 and suggest a mechanism for rapid fine-tuning of cortex structure and mechanics by adjusting the relative contribution of each nucleator.
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