Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration
Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration
复制标题
DOI：
10.1242/jcs.00600
复制
发表时间：
2003-07-15
影响因子：
4
通讯作者：
Murphy-Ullrich, JE
中科院分区：
文献类型：
--
作者：
Orr, AW;Elzie, CA;Murphy-Ullrich, JE
基质细胞外基质蛋白血小板反应蛋白-1（TSP 1）通过其肝素结合结构域中的一个序列（称为hep I肽）刺激粘着斑分解。这通过涉及钙网蛋白和低密度脂蛋白（LDL）受体相关蛋白（LRP）的受体共复合物介导信号传导。我们假设，这种过渡到一个中间的粘附状态增强细胞的动态环境条件下的反应。由于细胞粘附动力学影响细胞运动，我们问是否TSP 1/Hep I诱导的中间粘附改变细胞迁移。使用transwell和邓恩室测定，我们证明，TSP 1和Hep I梯度刺激内皮细胞趋化性。在没有梯度的情况下，用局部粘附不稳定浓度的TSP 1/hep I治疗增强了内皮细胞随机迁移或趋化作用，与细胞迁移、迁移速度和总细胞位移的增加相关。无钙网蛋白和无LRP的成纤维细胞不响应于TSP 1/hep 1而迁移，用LRP抑制剂受体相关蛋白（RAP）处理的内皮细胞也不迁移。此外，TSP 1/hep I诱导的粘着斑解体与碱性成纤维细胞生长因子（bFGF）的趋化性降低相关，但与酸性（a）FGF的趋化性增强相关，表明生长因子诱导的迁移的差异调节。因此，TSP 1/hep I刺激中间粘附调节内皮细胞和成纤维细胞的迁移表型，表明TSP 1在重塑反应中的作用。
The matricellular extracellular matrix protein thrombospondin-1 (TSP1) stimulates focal adhesion disassembly through a sequence (known as the hep I peptide) in its heparin-binding domain. This mediates signaling through a receptor co-complex involving calreticulin and low-density lipoprotein (LDL) receptor-related protein (LRP). We postulate that this transition to an intermediate adhesive state enhances cellular responses to dynamic environmental conditions. Since cell adhesion dynamics affect cell motility, we asked whether TSP1/hep I-induced intermediate adhesion alters cell migration. Using both transwell and Dunn chamber assays, we demonstrate that TSP1 and hep I gradients stimulate endothelial cell chemotaxis. Treatment with focal adhesion-labilizing concentrations of TSP1/hep I in the absence of a gradient enhances endothelial cell random migration, or chemokinesis, associated with an increase in cells migrating, migration speed, and total cellular displacement. Calreticulin-null and LRP-null fibroblasts do not migrate in response to TSP1/hep 1, nor do endothelial cells treated with the LRP inhibitor receptor-associated protein (RAP). Furthermore, TSP1/hep I-induced focal adhesion disassembly is associated with reduced chemotaxis to basic fibroblast growth factor (bFGF) but enhanced chemotaxis to acidic (a)FGF, suggesting differential modulation of growth factor-induced migration. Thus, TSP1/hep I stimulation of intermediate adhesion regulates the migratory phenotype of endothelial cells and fibroblasts, suggesting a role for TSP1 in remodeling responses.