Fibronectin regulates latent transforming growth factor-beta (TGF beta) by controlling matrix assembly of latent TGF beta-binding protein-1.
Fibronectin regulates latent transforming growth factor-beta (TGF beta) by controlling matrix assembly of latent TGF beta-binding protein-1.
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发表时间：
2005
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通讯作者：
S. Dallas;P. Sivakumar;Carolyn J. P. Jones;Qian Chen;D. M. Peters;D. Mosher;M. Humphries;C. Kielty
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作者：
S. Dallas;P. Sivakumar;Carolyn J. P. Jones;Qian Chen;D. M. Peters;D. Mosher;M. Humphries;C. Kielty
潜伏转化生长因子-β结合蛋白(LTBPs)是细胞外基质(ECM)中的糖蛋白，在ECM中储存潜伏的转化生长因子-β并调节其可获得性起主要作用。在这里，我们发现纤维连接蛋白对于LTBP1和转化生长因子-β(转化生长因子-β)进入成骨细胞和成纤维细胞的ECM是至关重要的。免疫定位研究表明，纤维连接蛋白提供了一种初始支架，该支架先于LTBP1沉积并形成模式，但LTBP1和纤维连接蛋白后来定位于单独的纤维网络中，这表明初始模板丢失。用抑制纤维连接蛋白组装的70 kDa N末端纤维连接蛋白片段处理胎鼠颅骨成骨细胞，会损害LTBP1和TGFbeta对细胞外基质的整合。与此一致的是，LTBP1未能在缺乏纤维连接蛋白基因的胚胎成纤维细胞中组装。LTBP1组装可以被全长纤维连接蛋白和超纤维连接蛋白拯救，它们能够组装成纤维连接蛋白原纤维，但不能被其他纤维连接蛋白片段拯救，包括一个含有160 kDa RGD的片段，它激活α5beta1整合素。这表明，LTBP1组装的关键事件是形成纤维连接蛋白纤维网络，仅由纤维连接蛋白分子连接整合素是不够的。纤维连接蛋白不仅对LTBP1进入ECM的初始整合是必不可少的，而且LTBP1的持续组装也需要纤维连接蛋白的持续存在。这些研究强调了纤维连接蛋白在LTBP1组装到ECM中的非冗余作用，并提示了纤维连接蛋白通过LTBP1相互作用调节转化生长因子β的新作用。
Latent transforming growth factor-beta-binding proteins (LTBPs) are extracellular matrix (ECM) glycoproteins that play a major role in the storage of latent TGF beta in the ECM and regulate its availability. Here we show that fibronectin is critical for the incorporation of LTBP1 and transforming growth factor-beta (TGF beta) into the ECM of osteoblasts and fibroblasts. Immunolocalization studies suggested that fibronectin provides an initial scaffold that precedes and patterns LTBP1 deposition but that LTBP1 and fibronectin are later localized in separate fibrillar networks, suggesting that the initial template is lost. Treatment of fetal rat calvarial osteoblasts with a 70-kDa N-terminal fibronectin fragment that inhibits fibronectin assembly impaired incorporation of LTBP1 and TGFbeta into the ECM. Consistent with this, LTBP1 failed to assemble in embryonic fibroblasts that lack the gene for fibronectin. LTBP1 assembly was rescued by full-length fibronectin and superfibronectin, which are capable of assembly into fibronectin fibrils, but not by other fibronectin fragments, including a 160-kDa RGD-containing fragment that activates alpha5beta1 integrins. This suggests that the critical event for LTBP1 assembly is the formation of a fibronectin fibrillar network and that integrin ligation by fibronectin molecules alone is not sufficient. Not only was fibronectin essential for the initial incorporation of LTBP1 into the ECM, but the continued presence of fibronectin was required for the continued assembly of LTBP1. These studies highlight a nonredundant role for fibronectin in LTBP1 assembly into the ECM and suggest a novel role for fibronectin in regulation of TGF beta via LTBP1 interactions.