Regulation of podosomes by integrin alphavbeta3 and Rho GTPase-facilitated phosphoinositide signaling.
Regulation of podosomes by integrin alphavbeta3 and Rho GTPase-facilitated phosphoinositide signaling.
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发表时间：
2006
影响因子：
6.6
通讯作者：
M. Chellaiah
中科院分区：
文献类型：
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作者：
M. Chellaiah
在破骨细胞中，磷脂酰肌醇 4,5 二磷酸 (PI(4,5)P2) 和磷脂酰肌醇 3,4,5 三磷酸 (PI(3,4,5)P3) 等多磷酸肌醇是响应整联蛋白 alphavbeta3 信号而产生的，它们在肌动蛋白细胞骨架重塑中发挥着关键作用。 Rho GTPase 分别通过激活磷脂酰肌醇 4-磷酸 5-激酶（PI4P-5 激酶）和磷脂酰肌醇 3-激酶（PI3 激酶）来调节 PI(4,5)P2 和 PI(3,4,5)P3 的水平。 PI(4,5)P2 与凝溶胶蛋白和 Wiscott-Aldrich 综合征蛋白 (WASP) 的相互作用对于破骨细胞中足小体的组装/拆卸和肌动蛋白环的形成至关重要。 PI(3,4,5)P3 与凝溶胶蛋白的相互作用可协调由几个关键信号分子组成的足体信号复合物。凝溶胶蛋白缺乏已被证明会阻碍小鼠破骨细胞的足小体组装和运动。然而，这些破骨细胞能够形成含有 WASP 的肌动蛋白环并保留其再吸收功能。 TAT 介导的凝溶胶蛋白磷酸肌醇结合域递送至破骨细胞中，导致足小体簇的产生并破坏肌动蛋白环的形成。因此，这些破骨细胞运动能力低下，吸收能力也较差。我们的观察表明，PI(4,5)P2 和 PI(3,4,5)P3 均通过调节肌动蛋白结合蛋白的切断、加帽和成核功能来调节破骨细胞功能。
In osteoclasts, polyphosphoinositides such as phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5 trisphosphate (PI(3,4,5)P3) are produced in response to integrin alphavbeta3 signaling and they have a critical role in actin cytoskeleton remodeling. The levels of PI(4,5)P2 and PI(3,4,5)P3 are regulated by Rho GTPase through the activation of phosphatidylinositol 4-phosphate 5-kinase (PI4P-5 kinase) and phospatidylinositol 3-kinase (PI3 kinase), respectively. Interaction of PI(4,5)P2 with gelsolin and Wiscott-Aldrich syndrome protein (WASP) is critical for podosome assembly/disassembly and actin ring formation in osteoclasts. Interaction of PI(3,4,5)P3 with gelsolin functions in orchestrating the podosome signaling complex consisting of several key signaling molecules. Gelsolin deficiency has been shown to block podosome assembly and motility in mouse osteoclasts. However, these osteoclasts are able to form a WASP-containing actin ring and retain their resorptive function. The TAT-mediated delivery of gelsolin phosphoinositide-binding domains into osteoclasts resulted in production of podosome clusters and disruption of actin ring formation. Hence, these osteoclasts were hypomotile and less resorptive. Our observations suggest that both PI(4,5)P2 and PI(3,4,5)P3 are involved in regulating osteoclast functions through modulation of severing, capping, and nucleating functions of actin-binding proteins.