Pallero Manuel A, Elzie Carrie A, Chen Jiping, Mosher Deane F, Murphy-Ullrich Joanne E
Department of Pathology, VH 668 1530 3rd Ave., South, Birmingham, AL 35294-0019, USA.
FASEB J. 2008 Nov;22(11):3968-79. doi: 10.1096/fj.07-104802. Epub 2008 Jul 24.
Anoikis, apoptotic cell death due to loss of cell adhesion, is critical for regulation of tissue homeostasis in tissue remodeling. Fibrogenesis is associated with reduced fibroblast apoptosis. The matricellular protein thrombospondin 1 (TSP1) regulates cell adhesion and motility during tissue remodeling and in fibrogenesis. The N-terminal domain of TSP1 binds to the calreticulin-LRP1 receptor co-complex to signal down-regulation of cell adhesion and increased cell motility through focal adhesion disassembly. TSP1 signaling through calreticulin-LRP1 activates cell survival signals such as PI3-kinase. Therefore, we tested the hypothesis that TSP1 supports cell survival under adhesion-independent conditions to facilitate tissue remodeling. Here, we show that platelet TSP1, its N-terminal domain (NoC1) as a recombinant protein, or a peptide comprising the calreticulin-LRP1 binding site [amino acids 17-35 (hep I)] in the N-terminal domain promotes fibroblast survival under anchorage-independent conditions. TSP1 activates Akt and decreases apoptotic signaling through caspase 3 and PARP1 in suspended fibroblasts. Inhibition of PI3K/Akt activity blocks TSP1-mediated anchorage-independent survival. Fibroblasts lacking LRP1 or expressing calreticulin lacking the TSP1 binding site do not respond to TSP1 with anchorage-independent survival. These data define a novel role for TSP1 signaling through the calreticulin/LRP1 co-complex in tissue remodeling and fibrotic responses through stimulation of anoikis resistance.-Pallero, M. A., Elzie, C. A., Chen, J., Mosher, D. F., Murphy-Ullrich, J. E. Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis.
失巢凋亡，即由于细胞黏附丧失导致的凋亡性细胞死亡，对于组织重塑过程中组织稳态的调节至关重要。纤维生成与成纤维细胞凋亡减少相关。基质细胞蛋白血小板反应蛋白1（TSP1）在组织重塑和纤维生成过程中调节细胞黏附与运动。TSP1的N端结构域与钙网蛋白-LRP1受体复合体能信号传导，通过粘着斑解体使细胞黏附下调并增加细胞运动。TSP1通过钙网蛋白-LRP1的信号传导激活细胞存活信号，如PI3激酶。因此，我们验证了TSP1在非黏附条件下支持细胞存活以促进组织重塑这一假说。在此，我们表明血小板TSP1、其作为重组蛋白的N端结构域（NoC1）或包含N端结构域中钙网蛋白-LRP1结合位点[氨基酸17 - 35（hep I）]的肽，在非锚定条件下可促进成纤维细胞存活。TSP1激活Akt并减少悬浮成纤维细胞中通过半胱天冬酶3和PARP1的凋亡信号传导。抑制PI3K/Akt活性可阻断TSP1介导的非锚定存活。缺乏LRP1或表达缺乏TSP1结合位点的钙网蛋白的成纤维细胞对TSP1介导的非锚定存活无反应。这些数据确定了TSP1通过钙网蛋白/LRP1复合体信号传导在组织重塑和纤维化反应中通过刺激失巢凋亡抗性发挥的新作用。-帕莱罗，M.A.，埃尔齐，C.A.，陈，J.，莫舍，D.F.，墨菲 - 乌尔里希，J.E.血小板反应蛋白1与钙网蛋白-LRP1结合发出失巢凋亡抗性信号。
