Requirement for Tyrosine Kinase-ERK1/2 Signaling in α1β1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells
Requirement for Tyrosine Kinase-ERK1/2 Signaling in α1β1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells
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大鼠系膜细胞 α1β1 整合素介导的胶原基质重塑中酪氨酸激酶-ERK1/2 信号传导的要求
DOI：
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Y. Kuroda
中科院分区：
文献类型：
--
作者：
S. Kagami;M. Urushihara;Shuji Kondo;K. Löster;W. Reutter;T. Tamaki;M. Yoshizumi;Y. Kuroda
肾小球系膜细胞（MCs）对系膜细胞外基质（ECM）的异常重塑是进行性肾小球肾炎（GN）的标志。我们最近发现，使用I型胶原凝胶收缩试验，α1β1整合素依赖性MC粘附和迁移是胶原基质重塑所必需的细胞行为。为了进一步确定α1β1整合素介导的胶原重塑的机制，我们研究了参与调节胶原凝胶收缩的MC的信号通路。免疫沉淀和磷酸酪氨酸检测显示，凝胶收缩与增强的活性和ERK 1/2的磷酸化MC。酪氨酸激酶抑制剂除莠霉素和金雀异黄素呈剂量依赖性抑制胶原凝胶收缩。此外，用MEK抑制剂PD 98059和反义ERK 1/2靶向ERK 1/2活性以剂量依赖性方式阻碍凝胶收缩。当在功能阻断性抗α1或抗β1整合素抗体存在下进行MC介导的凝胶收缩时，观察到对凝胶收缩和ERK 1/2磷酸化的类似抑制作用。细胞粘附和迁移实验表明，PD 98059和反义ERK 1/2阻断了α1β1整合素依赖的MC迁移，但不干扰胶原粘附，尽管在I型胶原上的细胞粘附中ERK 1/2磷酸化和ERK 1/2蛋白表达显著降低。上述因素均不影响α1β1整合素的膜表达。这些结果表明，ERK 1/2激活是关键的α1β1整合素依赖性MC迁移所必需的胶原基质重组。因此，我们得出结论，ERK 1/2可能作为一个可能的目标，药理学抑制病理性胶原基质形成的GN。
Abstract Abnormal mesangial extracellular matrix remodeling by mesangial cells (MCs) is the hallmark of progressive glomerulonephritis (GN). We recently showed, using a type I collagen gel contraction assay, that α1β1 integrin-dependent MC adhesion and migration are necessary cell behaviors for collagen matrix remodeling. To further determine the mechanism of α1β1 integrin-mediated collagen remodeling, we studied the signaling pathways of MCs that participate in the regulation of collagen gel contraction. Immunoprecipitation and phosphotyrosine detection revealed that gel contraction is associated with the enhanced activity and phosphorylation of ERK1/2 by MCs. The tyrosine kinase inhibitors herbimycin and genistein inhibited collagen gel contraction dose dependently. Furthermore, targeting ERK1/2 activity with a MEK inhibitor, PD98059, and antisense ERK1/2 hindered gel contraction in a dose-dependent manner. Similar inhibitory effects on gel contraction and ERK1/2 phosphorylation were observed when MC-mediated gel contraction was performed in the presence of function-blocking anti-α1 or anti-β1 integrin antibodies. However, cell adhesion and migration assays indicated that PD98059 and antisense ERK1/2 blocked α1β1 integrin-dependent MC migration, but did not interfere with collagen adhesion, although there was a marked decrease in ERK1/2 phosphorylation and ERK1/2 protein expression in cell adhesion on type I collagen. None of the above could affect membrane expression of α1β1 integrin. These results suggested that ERK1/2 activation is critical for the α1β1 integrin-dependent MC migration necessary for collagen matrix reorganization. We therefore conclude that ERK1/2 may serve as a possible target for pharmacological inhibition of pathological collagen matrix formation in GN.
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影响因子：
15.9
作者：
KAGAMI, S;BORDER, WA;NOBLE, NA
通讯作者：
NOBLE, NA
在哈布蛇毒引起的肾小球损伤中，系膜细胞迁移先于增殖。
DOI：
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发表时间：
1994
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
Barnes,JL;Hevey,KA;Hastings,RR;Bocanegra,RA
通讯作者：
Bocanegra,RA
DOI：
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发表时间：
1993-07
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
Shoji Kagami;W. A. Border;E. Ruoslahti;N. Noble
通讯作者：
Shoji Kagami;W. A. Border;E. Ruoslahti;N. Noble
通过转化生长因子-β 调节细胞粘附受体。
DOI：
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发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Heino,J;Ignotz,RA;Hemler,ME;Crouse,C;Massagué,J
通讯作者：
Massagué,J
影响因子：
19.6
作者：
Haseley, LA;Hugo, C;Johnson, RJ
通讯作者：
Johnson, RJ