Pi Xinchun, Ren Rongqin, Kelley Russell, Zhang Chunlian, Moser Martin, Bohil Aparna B, Divito Melinda, Cheney Richard E, Patterson Cam
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.
J Cell Biol. 2007 Dec 31;179(7):1569-82. doi: 10.1083/jcb.200704010. Epub 2007 Dec 24.
Endothelial cell migration is an important step during angiogenesis, and its dysregulation contributes to aberrant neovascularization. The bone morphogenetic proteins (BMPs) are potent stimulators of cell migration and angiogenesis. Using microarray analyses, we find that myosin-X (Myo10) is a BMP target gene. In endothelial cells, BMP6-induced Myo10 localizes in filopodia, and BMP-dependent filopodial assembly decreases when Myo10 expression is reduced. Likewise, cellular alignment and directional migration induced by BMP6 are Myo10 dependent. Surprisingly, we find that Myo10 and BMP6 receptor ALK6 colocalize in a BMP6-dependent fashion. ALK6 translocates into filopodia after BMP6 stimulation, and both ALK6 and Myo10 possess intrafilopodial motility. Additionally, Myo10 is required for BMP6-dependent Smad activation, indicating that in addition to its function in filopodial assembly, Myo10 also participates in a requisite amplification loop for BMP signaling. Our data indicate that Myo10 is required to guide endothelial migration toward BMP6 gradients via the regulation of filopodial function and amplification of BMP signals.
内皮细胞迁移是血管生成过程中的重要步骤，其失调会导致异常的新生血管形成。骨形态发生蛋白（BMPs）是细胞迁移和血管生成的有效刺激因子。通过微阵列分析，我们发现肌球蛋白-X（Myo10）是一个BMP靶基因。在内皮细胞中，BMP6诱导的Myo10定位于丝状伪足，当Myo10表达降低时，BMP依赖的丝状伪足组装减少。同样，BMP6诱导的细胞排列和定向迁移也依赖于Myo10。令人惊讶的是，我们发现Myo10和BMP6受体ALK6以BMP6依赖的方式共定位。BMP6刺激后，ALK6转位到丝状伪足中，并且ALK6和Myo10都具有丝状伪足内的运动性。此外，Myo10是BMP6依赖的Smad激活所必需的，这表明Myo10除了在丝状伪足组装中的功能外，还参与了BMP信号传导的必要放大环。我们的数据表明，Myo10通过调节丝状伪足功能和放大BMP信号来引导内皮细胞向BMP6梯度迁移。
