Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ
Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ
复制标题
DOI：
10.1242/jcs.073437
复制
发表时间：
2010-09-01
影响因子：
4
通讯作者：
Kielty, Cay M.
中科院分区：
文献类型：
--
作者：
Massam-Wu, Teresa;Chiu, Maybo;Kielty, Cay M.
控制生长因子TGF β的生物利用度对于组织形成和体内平衡是必不可少的，但确切地说，潜伏的TGF β是如何掺入细胞外基质的是未知的。在这里，我们表明，沉积的一个大的潜在的TGF β复合物（LLC），其中包含潜在的TGF β-结合蛋白1（LTBP-1），是直接依赖于在微纤维，与纤连蛋白相互作用在高阶fibrillogenesis的细胞周组装的TGF β。LTBP-1形成与微纤维共定位的细胞周阵列，而抑制蛋白敲低抑制纤维状LTBP-1和/或LLC沉积。阻断α 5 β 1整联蛋白或向培养物中补充肝素，这两者都能抑制微纤维组装，破坏LTBP-1沉积并增强Smad 2磷酸化。全长LTBP-1结合只有微弱的N-末端pro-glutarin-1，但这种协会强烈增强肝素。微原纤维相关糖蛋白MAGP-1（MFAP-2）抑制LTBP-1与原纤维蛋白-1的结合并刺激Smad 2磷酸化。相比之下，与全长LTBP-1强烈相互作用的fibulin-4不诱导Smad 2磷酸化。因此，LTBP-1和/或LLC沉积依赖于细胞周微纤维组装，并受LTBP-1、硫酸乙酰肝素、乙酰肝素-1和微纤维相关分子之间复杂相互作用的控制。以这种方式，微纤维控制TGF β的生物利用度。
Control of the bioavailability of the growth factor TGF beta is essential for tissue formation and homeostasis, yet precisely how latent TGF beta is incorporated into the extracellular matrix is unknown. Here, we show that deposition of a large latent TGF beta complex (LLC), which contains latent TGF beta-binding protein 1 (LTBP-1), is directly dependent on the pericellular assembly of fibrillin microfibrils, which interact with fibronectin during higher-order fibrillogenesis. LTBP-1 formed pericellular arrays that colocalized with microfibrils, whereas fibrillin knockdown inhibited fibrillar LTBP-1 and/or LLC deposition. Blocking alpha 5 beta 1 integrin or supplementing cultures with heparin, which both inhibited microfibril assembly, disrupted LTBP-1 deposition and enhanced Smad2 phosphorylation. Full-length LTBP-1 bound only weakly to N-terminal pro-fibrillin-1, but this association was strongly enhanced by heparin. The microfibril-associated glycoprotein MAGP-1 (MFAP-2) inhibited LTBP-1 binding to fibrillin-1 and stimulated Smad2 phosphorylation. By contrast, fibulin-4, which interacted strongly with full-length LTBP-1, did not induce Smad2 phosphorylation. Thus, LTBP-1 and/or LLC deposition is dependent on pericellular microfibril assembly and is governed by complex interactions between LTBP-1, heparan sulfate, fibrillin-1 and microfibril-associated molecules. In this way, microfibrils control TGF beta bioavailability.