Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts
Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts
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DOI：
10.1242/jcs.03271
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发表时间：
2006-12-01
影响因子：
4
通讯作者：
Geiger, Benjamin
中科院分区：
文献类型：
--
作者：
Luxenburg, Chen;Parsons, J. Thomas;Geiger, Benjamin
破骨细胞是一种多核的大细胞，在破骨细胞极化过程中，破骨细胞的足状体从分散分布到形成簇状和环状超结构，再到在细胞周围形成封闭带，从而使破骨细胞降解。在本研究中，我们证明了在培养的破骨细胞中，足体相关肌动蛋白的水平及其重组在足体环形成后急剧增加。在外周环，肌动蛋白水平和动态重组高，而桩蛋白，与相同的粘附超结构，保持相对稳定。这些动态变化受酪氨酸激酶pp 60 c-Src的调节，其支架活性支持未成熟的稳定的podosomes的组装;其催化活性是podosomes成熟和营业额所必需的。破骨细胞极化过程中增强的足粒动态重组与Src底物corpine的酪氨酸磷酸化的局部水平呈负相关。此外，过度表达的coronin，突变在其主要Src磷酸化位点，增强肌动蛋白营业额，表明在极化破骨细胞的podosome动力学是由于下调coronin活性的Src依赖性磷酸化。
Osteoclasts are large, multinucleated cells that adhere to bone via podosomes, and degrade it. During osteoclast polarization, podosomes undergo reorganization from a scattered distribution, through the formation of clusters and ring super-structures, to the assembly of a sealing zone at the cell periphery. In the present study, we demonstrate that the levels of podosome-associated actin, and its reorganization in cultured osteoclasts, radically increase upon formation of podosome rings. At the peripheral ring, actin levels and dynamic reorganization were high, whereas paxillin, associated with the same adhesion super-structure, remained relatively stable. These dynamic changes were regulated by the tyrosine kinase pp60c-Src, whose scaffolding activity supported the assembly of immature stationary podosomes; its catalytic activity was essential for podosome maturation and turnover. The enhanced dynamic reorganization of podosomes during osteoclast polarization was inversely related to the local levels of tyrosine phosphorylation of the Src substrate, cortactin. Furthermore, overexpression of cortactin, mutated at its major Src phosphorylation sites, enhanced actin turnover, suggesting that podosome dynamics in polarizing osteoclasts are attributable to the downregulation of cortactin activity by its Src-dependent phosphorylation.