The role of p42/44 MAPK and protein kinase B in connective tissue growth factor induced extracellular matrix protein production, cell migration, and actin cytoskeletal rearrangement in human mesangial cells
The role of p42/44 MAPK and protein kinase B in connective tissue growth factor induced extracellular matrix protein production, cell migration, and actin cytoskeletal rearrangement in human mesangial cells
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DOI：
10.1074/jbc.m203715200
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发表时间：
2002-11-15
影响因子：
4.8
通讯作者：
Brady, HR
中科院分区：
文献类型：
--
作者：
Crean, JKG;Finlay, D;Brady, HR
结缔组织生长因子（CTGF）是一个新兴的立即早期基因产物家族的成员，在分化和组织修复过程中协调复杂的生物学过程。在这里，我们描述了CTGF在整合素介导的粘附信号和细胞外基质成分在人系膜细胞的生产中的作用。此外，CTGF的原代系膜细胞诱导纤维连接蛋白的生产，细胞迁移和细胞骨架重排。这些功能反应与Src的募集和p42/44 MAPK和蛋白激酶B的磷酸化有关。抑制CTGF诱导的p42/44 MAPK或磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B途径活性可消除纤连蛋白表达的诱导。此外，抗β 3整联蛋白抗体减弱了p42/44 MAPK和蛋白激酶B的激活以及纤连蛋白水平的增加。CTGF还通过β（3）整合素依赖性机制诱导肾小球系膜细胞迁移，该机制对p42/44 MAPK和PI 3 K途径的抑制同样敏感，并且CTGF通过上调β（3）整合素促进肾小球系膜细胞与I型胶原的粘附。瞬时肌动蛋白细胞骨架解体后观察到的配体治疗过程中的24小时内。CTGF诱导肾小球系膜细胞的局灶性粘附的丧失，如点状黏着斑蛋白的丧失所证明的。然而，这些过程是p42/44 MAPK和PI 3 K途径独立的。我们的数据支持这一假设，CTGF介导的一些生物学效应的诱导信号转导过程通过β（3）整合素。然而，其他如肌动蛋白细胞骨架分解以β（3）、整合素/MALPK/PI 3 K非依赖性方式调节，表明CTGF是一种复杂的多效性因子，具有放大原发性病理生理反应的潜力。
Connective tissue growth factor (CTGF) is a member of an emerging family of immediate-early gene products that coordinate complex biological processes during differentiation and tissue repair. Here we describe the role of CTGF in integrin-mediated adhesive signaling and the production of extracellular matrix components in human mesangial cells. The addition of CTGF to primary mesangial cells induced fibronectin production, cell migration, and cytoskeletal rearrangement. These functional responses were associated with recruitment of Src and phosphorylation of p42/44 MAPK and protein kinase B. The inhibition of CTGF-induced p42/44 MAPK or phosphatidylinositol 3-kinase (PI3K)/protein kinase B pathway activities abrogated the induction of fibronectin expression. In addition, anti-beta(3) integrin antibodies attenuated the activation of both the p42/44 MAPK and protein kinase B and the increase in fibronectin levels. CTGF also induced mesangial cell migration via a beta(3) integrin-dependent mechanism that was similarly sensitive to the inhibition of the p42/44 MAPK and PI3K pathways, and it promoted the adhesion of the mesangial cells to type I collagen via up-regulation of a, integrin. Transient actin cytoskeletal disassembly was observed following treatment with the ligand over the course of a 24-h period. CTGF induced the loss of focal adhesions from the mesangial cell as evidenced by the loss of punctate vinculin. However, these processes are p42/44 MAPK and PI3K pathway-independent. Our data support the hypothesis that CTGF mediates a number of its biological effects by the induction of signaling processes via beta(3) integrin. However, others such as actin cytoskeleton disassembly are modulated in a beta(3), integrin/MALPK/PI3K-independent manner, indicating that CTGF is a complex pleiotropic factor with the potential to amplify primary pathophysiological responses.