Integrin α8β1 mediates adhesion to LAP-TGFβ1
Integrin α8β1 mediates adhesion to LAP-TGFβ1
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DOI：
10.1242/jcs.00145
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发表时间：
2002-12-01
影响因子：
4
通讯作者：
Schnapp, LM
中科院分区：
文献类型：
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作者：
Lu, M;Munger, JS;Schnapp, LM
纤维化的发展是对各种损伤的常见反应，并导致基质蛋白的净积累和正常器官功能的损害。我们先前报道，整合素α8β1在正常肺组织中由肺泡间质细胞表达，并在纤维化的发生发展过程中上调。TGFbeta1是肺纤维化炎症反应的重要介质。TGFbeta1是一种潜伏蛋白，与潜伏期相关肽(LAP)非共价相关，需要激活才能发挥作用。LAP-TGFbeta1和LAP-TGFbeta3含有精氨酸-甘氨酸-天冬氨酸(RGD)三肽序列，这是一个已知的整合素识别基序。整合素α8beta1通过RGD序列与纤维连接蛋白和玻璃体连接蛋白等多种配体结合。最近的研究表明，整合素Alphavbeta1、Alphavbeta6和Alphavbeta8通过RGD位点与LAP-TGFbeta1结合。因此，我们询问LAP-TGFbeta1是否可能是α8beta1的配体，以及这是否可能在纤维化的发展中起重要作用。我们发现，转Alpha8亚基的细胞系在重组LAP-TGFbeta1上的铺展和黏附能力明显好于模型转染组。Alpha8转染组细胞对LAP-TGFbeta3的黏附能力也明显好于假手术组。通过Mn2+或整合素Beta1激活抗体8A2激活α8beta1，可增强与LAP-TGFbeta1的粘附性。此外，当我们使用RGD位点突变为RGE的重组LAP-TGFbeta1蛋白时，细胞黏附被取消。α8beta1与LAP-TGFbeta1结合可促进细胞增殖，促进FAK和ERK的磷酸化，但不激活TGFbeta1。这些数据强烈表明LAP-TGFbeta1是α8β1的配体，α8β1与LAP-TGFbeta1的相互作用可能会影响细胞的行为。
The development of fibrosis is a common response to a variety of injuries and results in the net accumulation of matrix proteins and impairment of normal organ function. We previously reported that the integrin alpha8beta1 is expressed by alveolar interstitial cells in normal lung and is upregulated during the development of fibrosis. TGFbeta1 is an important mediator of the inflammatory response in pulmonary fibrosis. TGFbeta1 is secreted as a latent protein that is non-covalently associated with latency-associated peptide (LAP) and requires activation to exert its effects. LAP-TGFbeta1 and LAP-TGFbeta3 contain the tripeptide sequence, arginine-glycine-aspartic acid (RGD), a known integrin recognition motif. The integrin alpha8beta1 binds to several ligands such as fibronectin and vitronectin through the RGD sequence. Recent reports demonstrate that the integrins alphavbeta1, alphavbeta6 and alphavbeta8 adhere to LAP-TGFbeta1 through the RGD site. Therefore, we asked whether LAP-TGFbeta1 might be a ligand for alpha8beta1 and whether this may be important in the development of fibrosis. We found that cell lines transfected with alpha8 subunit were able to spread on and adhere to recombinant LAP-TGFbeta1 significantly better than mock transfected cell lines. alpha8-transfected cells were also able to adhere to LAP-TGFbeta3 significantly better than mock transfected cells. Adhesion to LAP-TGFbeta1 was enhanced by activation of alpha8beta1 by Mn2+, or 8A2, an integrin beta1 activating antibody. Furthermore, cell adhesion was abolished when we used a recombinant LAP-TGFbeta1 protein in which the RGD site was mutated to RGE. alpha8beta1 binding to LAP-TGFbeta1 increased cell proliferation and phosphorylation of FAK and ERK, but did not activate of TGFbeta1. These data strongly suggest that LAP-TGFbeta1 is a ligand of alpha8beta1 and interaction of alpha8beta1 with LAP-TGFbeta1 may influence cell behavior.