Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion.
Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion.
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DOI：
10.1016/j.cub.2011.06.065
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发表时间：
2011-09-13
期刊：
影响因子：
--
通讯作者：
Weaver AM
中科院分区：
文献类型：
--
作者：
Sung BH;Zhu X;Kaverina I;Weaver AM
分支肌动蛋白组装对于细胞运动和膜运输都是至关重要的。分支肌动蛋白调节剂corneumen通常被认为通过控制前缘片状脂质动力学来促进细胞迁移。然而，最近的报告表明，板状伪足是不需要细胞运动，这表明了一种替代机制。由于皮质激素也调节膜运输和粘附动力学，我们假设细胞外基质（ECM）和/或整合素运输的分泌改变可能是皮质激素敲低（KD）细胞运动缺陷的基础。与ECM分泌中的主要缺陷一致，皮质素-KD细胞的运动性和板状脂质缺陷通过在增加浓度的外源性ECM上铺板而被完全拯救。此外，皮质素-KD细胞速度缺陷在由对照细胞产生的无细胞自分泌ECM上被拯救，但在由皮质素-KD细胞产生的ECM上不被拯救。调查的机制表明，而内吞FN再沉积在基底细胞表面的控制细胞，皮质素KD细胞表现出缺陷FN分泌和异常FN保留在后期内吞/溶酶体室。皮质素-KD运动和FN沉积缺陷在溶酶体融合调节剂Synaptotagmin-7的对照细胞中由KD表型模仿。通过表达皮质素结合结构域突变体来拯救皮质素-KD细胞揭示了与Arp 2/3复合物和肌动蛋白丝的相互作用对于拯救细胞运动性和自分泌ECM分泌表型是必不可少的，而不需要SH 3结构域伴侣的结合。由支链肌动蛋白网络的coreolin调节促进的有效细胞运动性涉及从晚期内体/溶酶体隔室加工和切除内化的ECM。
Branched actin assembly is critical for both cell motility and membrane trafficking. The branched actin regulator, cortactin, is generally considered to promote cell migration by controlling leading edge lamellipodial dynamics. However, recent reports indicate that lamellipodia are not required for cell movement, suggesting an alternate mechanism. Since cortactin also regulates membrane trafficking and adhesion dynamics, we hypothesized that altered secretion of extracellular matrix (ECM) and/or integrin trafficking might underlie motility defects of cortactin-knockdown (KD) cells. Consistent with a primary defect in ECM secretion, both motility and lamellipodial defects of cortactin-KD cells were fully rescued by plating on increasing concentrations of exogenous ECM. Furthermore, cortactin-KD cell speed defects were rescued on cell-free autocrine ECM produced by control cells but not on ECM produced by cortactin-KD cells. Investigation of the mechanism revealed that whereas endocytosed FN is redeposited at the basal cell surface by control cells, cortactin-KD cells exhibit defective FN secretion and abnormal FN retention in a late endocytic/lysosomal compartment. Cortactin-KD motility and FN deposition defects were phenocopied by KD in control cells of the lysosomal fusion regulator Synaptotagmin-7. Rescue of cortactin-KD cells by expression of cortactin binding domain mutants revealed that interaction with Arp2/3 complex and actin filaments is essential for rescue of both cell motility and autocrine ECM secretion phenotypes whereas binding of SH3 domain partners is not required. Efficient cell motility, promoted by cortactin regulation of branched actin networks, involves processing and resecretion of internalized ECM from a late endosomal/lysosomal compartment.
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影响因子：
30.5
作者：
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影响因子：
9.2
作者：
Kinley, AW;Weed, SA;Parsons, JT
通讯作者：
Parsons, JT
影响因子：
3.7
作者：
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通讯作者：
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DOI：
10.1083/jcb.200408165
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
Mellman I