Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells
Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells
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DOI：
10.1073/pnas.1002309107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Roy, Partha
中科院分区：
文献类型：
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作者：
Bae, Yong Ho;Ding, Zhijie;Roy, Partha
Profilin1是一种普遍表达的肌动蛋白结合蛋白，通过肌动蛋白细胞骨架调控在细胞迁移中起关键作用。鉴于传统观点认为profilin1是一种促迁移分子，很难调和profilin1在各种侵袭性腺癌中下调以及profilin1表达减少实际上使某些腺癌细胞的移动性增加的观察结果。在本研究中，我们发现profilin1在MDA-MB-231乳腺癌细胞和正常细胞中负调控lamellipodin靶向到前沿；profilin1的缺失增加了板足尖端（与Ena/VASP结合的地方）的板足素浓度，这介导了高运动性。我们报道了profilin1调节板足素定位的分子机制与磷酸肌苷控制有关。具体来说，我们发现磷酸化肌苷结合profilin1通过负性调节膜上的PI(3,4)P-2抑制MDA-MB-231细胞的运动，从而限制lamellipodin [PI(3,4)P-2结合蛋白]和Ena/VASP向边缘的募集。总之，本研究揭示了profilin1-磷酸肌苷相互作用的独特生物学后果，从而为profilin1独立于其肌动蛋白相关活性调控细胞迁移提供了直接证据。
Profilin1, a ubiquitously expressed actin-binding protein, plays a critical role in cell migration through actin cytoskeletal regulation. Given the traditional view of profilin1 as a promigratory molecule, it is difficult to reconcile observations that profilin1 is down-regulated in various invasive adenocarcinomas and that reduced profilin1 expression actually confers increased motility to certain adenocarcinoma cells. In this study, we show that profilin1 negatively regulates lamellipodin targeting to the leading edge in MDA-MB-231 breast cancer cells and normal cells; profilin1 depletion increases lamellipodin concentration at the lamellipodial tip (where it binds Ena/VASP), and this mediates the hypermotility. We report that the molecular mechanism underlying profilin1's modulation of lamellipodin localization relates to phosphoinositide control. Specifically, we show that phosphoinositide binding of profilin1 inhibits the motility of MDA-MB-231 cells by negatively regulating PI(3,4)P-2 at the membrane and thereby limiting recruitment of lamellipodin [a PI(3,4)P-2-binding protein] and Ena/VASP to the leading edge. In summary, this study uncovers a unique biological consequence of profilin1-phosphoinositide interaction, thus providing direct evidence of profilin1's regulation of cell migration independent of its actin-related activity.