Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.
Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.
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作者：
癌症侵袭是转移的标志。癌细胞侵袭的间充质模式由分支的F-肌动蛋白网络的组装驱动的伸长的膜突起介导。肌动蛋白调节器的失调如何促进癌细胞侵袭仍然是个谜。我们报道了肌动蛋白调节因子Lamellipodin的表达和膜定位的增加与乳腺癌患者无转移生存率的降低和预后不良相关。与此一致，我们发现在原位小鼠乳腺癌模型中，Lamellipodin耗竭减少了肺转移。侵袭性3D癌细胞迁移以及侵袭伪足形成和基质降解在层状脂质蛋白耗尽后受损。从机制上讲，我们表明Lamellipodin通过肌动蛋白延长Ena/VASP蛋白和刺激肌动蛋白分支的Scar/WAVE复合物促进侵入性3D癌细胞迁移。相比之下，随机2D细胞迁移需要Lamellipodin与Scar/WAVE而不是Ena/VASP的相互作用。我们确定了一种磷酸化依赖性机制，调节这些效应物的选择性招募到Lamellipodin：Src介导的Lamellipodin磷酸化促进其与Scar/WAVE和Ena/VASP的结合，而Src依赖性磷酸化增强与Scar/WAVE的结合，但不增强与Ena/VASP的结合。通过这些选择性的、受调节的相互作用，Lamellipodin介导表皮生长因子（EGF）梯度的定向传感和乳腺癌细胞的侵入性3D迁移。我们的研究结果表明，增加Lamellipodin水平增强Ena/VASP和Scar/WAVE在质膜上的活性，以促进3D侵袭和转移。
Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.
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用于定量细胞迁移，突起和荧光强度的开源软件。
DOI：
10.1083/jcb.201501081
发表时间：
2015-04-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Barry DJ;Durkin CH;Abella JV;Way M
通讯作者：
Way M
影响因子：
6.6
作者：
Beaty, Brian T.;Condeelis, John
通讯作者：
Condeelis, John
影响因子：
4.8
作者：
Barzik, M;Kotova, TI;Schafer, DA
通讯作者：
Schafer, DA
影响因子：
16.2
作者：
Koleske, AJ;Gifford, AM;Baltimore, D
通讯作者：
Baltimore, D
DOI：
10.1083/jcb.201003014
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hansen SD;Mullins RD
通讯作者：
Mullins RD