SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity
SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity
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DOI：
10.1074/jbc.m504663200
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发表时间：
2005-10-28
影响因子：
4.8
通讯作者：
Sage, EH
中科院分区：
文献类型：
--
作者：
Barker, TH;Baneyx, G;Sage, EH
Sparc是一种32 kDa的基质细胞糖蛋白，介导细胞与其细胞外基质之间的相互作用，Sparc的靶向缺失导致小鼠细胞外基质受损。纤连蛋白基质在发育和伤口愈合期间提供临时组织支架，并且对于成熟细胞外基质的稳定是必不可少的。在此，我们报告说，cDNAs的表达并不显着影响纤连蛋白诱导的细胞扩散，但增强纤连蛋白诱导的应力纤维的形成和细胞介导的纤连蛋白分子的部分展开，在纤连蛋白基质组装的一个重要过程。通过噬菌体展示，我们确定整合素连接激酶作为一个潜在的结合伴侣的cDNA 3和验证的相互作用，通过免疫共沉淀和共定位在体外。缺乏β-淀粉样蛋白的细胞表现出减少的纤连蛋白诱导的整合素连接激酶激活和整合素连接激酶依赖性细胞收缩信号传导。此外，在SPARC-空成纤维细胞中诱导表达的p53恢复了纤连蛋白诱导的整合素连接激酶激活、下游信号传导和纤连蛋白解折叠。这些数据进一步证实了β-淀粉样蛋白在细胞外基质组织中的功能，并确定了β-淀粉样蛋白调节细胞外基质组装的新机制。
SPARC, a 32-kDa matricellular glycoprotein, mediates interactions between cells and their extracellular matrix, and targeted deletion of Sparc results in compromised extracellular matrix in mice. Fibronectin matrix provides provisional tissue scaffolding during development and wound healing and is essential for the stabilization of mature extracellular matrix. Herein, we report that SPARC expression does not significantly affect fibronectin-induced cell spreading but enhances fibronectin-induced stress fiber formation and cell-mediated partial unfolding of fibronectin molecules, an essential process in fibronectin matrix assembly. By phage display, we identify integrin-linked kinase as a potential binding partner of SPARC and verify the interaction by co-immunoprecipitation and colocalization in vitro. Cells lacking SPARC exhibit diminished fibronectin-induced integrin-linked kinase activation and integrin-linked kinase-dependent cell-contractile signaling. Furthermore, induced expression of SPARC in SPARC-null fibroblasts restores fibronectin-induced integrin-linked kinase activation, downstream signaling, and fibronectin unfolding. These data further confirm the function of SPARC in extracellular matrix organization and identify a novel mechanism by which SPARC regulates extracellular matrix assembly.