Evidence for a functional association between phosphatidylinositol 3-kinase and c-src in the spreading response of osteoclasts to colony-stimulating factor-1.
Evidence for a functional association between phosphatidylinositol 3-kinase and c-src in the spreading response of osteoclasts to colony-stimulating factor-1.
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DOI：
10.1210/endo.141.6.7480
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发表时间：
2000-06
期刊：
影响因子：
4.8
通讯作者：
A. Grey;Y. Chen;I. Paliwal;K. Carlberg;K. Insogna
中科院分区：
文献类型：
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作者：
A. Grey;Y. Chen;I. Paliwal;K. Carlberg;K. Insogna
破骨细胞是骨吸收细胞，其正常功能部分取决于它们在骨表面上迁移以启动新的骨吸收位点的能力。生长因子/细胞因子，集落刺激因子-1（CSF-1），以c-src依赖的方式有效刺激破骨细胞运动。与c-src一起参与CSF-1诱导的破骨细胞细胞骨架重塑的细胞内信号分子尚未确定。在这里，我们证明，使用抑制剂渥曼青霉素和LY 294002，磷脂酰肌醇3-激酶（PI 3-K）的激活所需的CSF-1诱导的破骨细胞的蔓延。在CSF-1处理破骨细胞样细胞后，与CSF-1受体c-fms相关的PI 3-K活性增加，并且PI 3-K的85-kDa调节亚基和c-src共免疫沉淀。CSF-1诱导PI 3-K向细胞周边的再分布。p85和c-src之间的关联部分是由于p85的富含脯氨酸的序列和c-src的SH 3结构域之间的直接相互作用。在体外，c-src SH 3结构域刺激PI 3-K活性。综上所述，目前的数据表明，c-src，通过其SH 3结构域，可能参与CSF-1诱导的PI 3-K的激活，PI 3-K和c-src是在信号通路，维护CSF-1诱导的破骨细胞的细胞骨架的变化。
Osteoclasts are bone-resorbing cells whose normal function depends in part upon their ability to migrate over the bone surface to initiate new sites of bone resorption. The growth factor/cytokine, colony-stimulating factor-1 (CSF-1), potently stimulates osteoclast motility, in a c-src-dependent fashion. The intracellular signaling molecules that participate with c-src in CSF-1-induced remodeling of the osteoclast cytoskeleton have not been identified. Here we demonstrate, using the inhibitors wortmannin and LY294002, that activation of phosphatidylinositol 3-kinase (PI3-K) is required for CSF-1-induced spreading in osteoclasts. After CSF-1 treatment of osteoclast-like cells, PI3-K activity associated with the CSF-1 receptor c-fms, is increased, and the 85-kDa regulatory subunit of PI3-K and c-src coimmunoprecipitate. CSF-1 induces redistribution of PI3-K to the periphery of the cell. The association between p85 and c-src is due in part to a direct interaction between the proline-rich sequences of p85 and the SH3 domain of c-src. In vitro, the c-src SH3 domain stimulates PI3-K activity. Taken together, the current data suggest that c-src, via its SH3 domain, may participate in CSF-1-induced activation of PI3-K and that PI3-K and c-src are in the signaling pathway that subserves CSF-1-induced cytoskeletal changes in osteoclasts.