p27kip1 Controls Cell Morphology and Motility by Regulating Microtubule-Dependent Lipid Raft Recycling
p27kip1 Controls Cell Morphology and Motility by Regulating Microtubule-Dependent Lipid Raft Recycling
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DOI：
10.1128/mcb.00723-09
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发表时间：
2010-05-01
影响因子：
5.3
通讯作者：
Baldassarre, Gustavo
中科院分区：
文献类型：
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作者：
Belletti, Barbara;Pellizzari, Ilenia;Baldassarre, Gustavo
P27(Kip1)(P27)是细胞周期蛋白/细胞周期蛋白依赖性激酶复合体的抑制因子，其核丢失预示着多种实体肿瘤预后不良。当p27位于细胞质中时，它与OP18/stathmin(Stathmin)结合，并抑制其活性。OP18/stathmin是一种微管破坏蛋白。这会导致MT的稳定，从而对细胞迁移产生负面影响。在这里，我们证明这个p27功能也影响浸泡在三维(3D)基质中的细胞的形态和运动性。缺乏p27的细胞显示MT稳定性降低，在3D环境中呈圆形，在其运动模式下表现为间充质-阿米巴转化。当细胞与细胞外基质接触时，在p27缺失细胞中观察到的MT稳定性降低导致脂筏运输加速和RhoA活性增加。重要的是，细胞形态、运动性、MT网络组成和p27缺失细胞的分布被伴随着stathmin的基因消融所挽救，这意味着p27和stathmin的平衡表达是3D环境中细胞骨架组织和细胞行为的关键决定因素。
p27(kip1) (p27) is an inhibitor of cyclin/cyclin-dependent kinase complexes, whose nuclear loss indicates a poor prognosis in various solid tumors. When located in the cytoplasm, p27 binds Op18/stathmin (stathmin), a microtubule (MT)-destabilizing protein, and restrains its activity. This leads to MT stabilization, which negatively affects cell migration. Here, we demonstrate that this p27 function also influences morphology and motility of cells immersed in three-dimensional (3D) matrices. Cells lacking p27 display a decrease in MT stability, a rounded shape when immersed in 3D environments, and a mesenchymal-amoeboid conversion in their motility mode. Upon cell contact to extracellular matrix, the decreased MT stability observed in p27 null cells results in accelerated lipid raft trafficking and increased RhoA activity. Importantly, cell morphology, motility, MT network composition, and distribution of p27 null cells were rescued by the concomitant genetic ablation of Stathmin, implicating that the balanced expression of p27 and stathmin represents a crucial determinant for cytoskeletal organization and cellular behavior in 3D contexts.