c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis.
c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis.
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DOI：
10.1016/j.cub.2010.03.048
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发表时间：
2010-05-11
期刊：
影响因子：
--
通讯作者：
Krause M
中科院分区：
文献类型：
--
作者：
Michael M;Vehlow A;Navarro C;Krause M
细胞运动的严格调节对许多生理过程至关重要，如功能性神经系统的形成和伤口愈合。果蝇Abl在果蝇神经元发育过程中负调控肌动蛋白细胞骨架效应蛋白Ena，并且已经假设这可能通过未知的中介发生。Lamellipodin （Lpd）调节细胞运动，将Ena/VASP蛋白（Ena, Mena， VASP， EVL）募集到细胞边缘。然而，对这种征聘的管理仍未得到解决。我们发现Lpd是Abl激酶的底物，并与Abl SH2结构域结合。Lpd的磷酸化正调控Lpd与Ena/VASP蛋白之间的相互作用。始终如一地，将Mena和EVL有效地招募到Lpd的前沿需要Abl激酶。此外，netrin-1刺激初级皮质神经元时，Abl激酶对Lpd的短暂磷酸化与Lpd- mena共沉淀的增加呈正相关。Lpd也在血小板衍生生长因子（PDGF）刺激下被Abl激酶短暂磷酸化，调节PDGF诱导的成纤维细胞背褶和轴突形态发生，并以依赖于Ena/ vasp的方式与c-Abl合作。我们的研究结果表明，Abl激酶积极调节Lpd-Ena/VASP相互作用，Ena/VASP向Lpd的前缘募集，以及Lpd-Ena/VASP在轴突形态发生和pdgf诱导的背褶中的功能。我们的数据不支持Abl对Ena的负调控作用。相反，我们认为Lpd是迄今为止未知的Abl和Ena/VASP蛋白之间的中介。►在PDGF和netrin刺激下，Abl激酶可瞬时磷酸化Lpd►c-Abl磷酸化Lpd可积极调节Lpd-Ena/VASP相互作用►Lpd、Ena/VASP蛋白和Abl激酶可调节成纤维细胞的背褶褶皱►c-Abl和Lpd以依赖于Ena/VASP的方式促进轴突形态形成
Tight regulation of cell motility is essential for many physiological processes, such as formation of a functional nervous system and wound healing. Drosophila Abl negatively regulates the actin cytoskeleton effector protein Ena during neuronal development in flies, and it has been postulated that this may occur through an unknown intermediary. Lamellipodin (Lpd) regulates cell motility and recruits Ena/VASP proteins (Ena, Mena, VASP, EVL) to the leading edge of cells. However, the regulation of this recruitment has remained unsolved. Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. Consistently, efficient recruitment of Mena and EVL to Lpd at the leading edge requires Abl kinases. Furthermore, transient Lpd phosphorylation by Abl kinases upon netrin-1 stimulation of primary cortical neurons positively correlates with an increase in Lpd-Mena coprecipitation. Lpd is also transiently phosphorylated by Abl kinases upon platelet-derived growth factor (PDGF) stimulation, regulates PDGF-induced dorsal ruffling of fibroblasts and axonal morphogenesis, and cooperates with c-Abl in an Ena/VASP-dependent manner. Our findings suggest that Abl kinases positively regulate Lpd-Ena/VASP interaction, Ena/VASP recruitment to Lpd at the leading edge, and Lpd-Ena/VASP function in axonal morphogenesis and in PDGF-induced dorsal ruffling. Our data do not support the suggested negative regulatory role of Abl for Ena. Instead, we propose that Lpd is the hitherto unknown intermediary between Abl and Ena/VASP proteins. ► Abl kinases transiently phosphorylate Lpd upon PDGF and netrin stimulation ► Phosphorylation of Lpd by c-Abl positively regulates Lpd-Ena/VASP interaction ► Lpd, Ena/VASP proteins, and Abl kinases regulate dorsal ruffling of fibroblasts ► c-Abl and Lpd promote axonal morphogenesis in an Ena/VASP-dependent manner
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