Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Biophys Res Commun. 2010 Jul 30;398(3):525-31. doi: 10.1016/j.bbrc.2010.06.112. Epub 2010 Jul 1.
Transforming growth factor-beta 1 (TGF-beta1) is secreted as a latent complex, which consists of latency-associated peptide (LAP) and the mature ligand. The release of the mature ligand from LAP usually occurs through conformational change of the latent complex and is therefore considered to be the first step in the activation of the TGF-beta signaling pathway. So far, factors such as heat, pH changes, and proteolytic cleavage are reportedly involved in this activation process, but the precise molecular mechanism is still far from clear. Identification and characterization of the cell surface proteins that bind to LAP are important to our understanding of the latent TGF-beta activation process. In this study, we have identified heat shock protein 90 beta (HSP90beta) from the cell surface of the MG63 osteosarcoma cell line as a LAP binding protein. We have also found that MG63 cells secrete HSP90beta into extracellular space which inhibits the activation of latent TGF-beta1, and that there is a subsequent decrease in cell proliferation. TGF-beta1-mediated stimulation of MG63 cells resulted in the increased cell surface expression of HSP90beta. Thus, extracellular HSP90beta is a negative regulator for the activation of latent TGF-beta1 modulating TGF-beta signaling in the extracellular domain.
转化生长因子-β1（TGF-β1）以前体复合物的形式分泌，该复合物由潜伏相关肽（LAP）和成熟配体组成。成熟配体从 LAP 中的释放通常通过前体复合物的构象变化发生，因此被认为是 TGF-β信号通路激活的第一步。到目前为止，已有报道称热、pH 值变化和蛋白水解切割等因素参与了这一激活过程，但确切的分子机制仍远未清楚。鉴定和表征与 LAP 结合的细胞表面蛋白对于我们理解潜伏 TGF-β的激活过程很重要。在这项研究中，我们从骨肉瘤 MG63 细胞系的细胞表面鉴定出热休克蛋白 90β（HSP90β）是 LAP 结合蛋白。我们还发现 MG63 细胞将 HSP90β分泌到细胞外空间，从而抑制潜伏 TGF-β1 的激活，并且细胞增殖随后减少。TGF-β1 介导的 MG63 细胞刺激导致细胞表面 HSP90β表达增加。因此，细胞外 HSP90β是调节细胞外域潜伏 TGF-β1 激活的 TGF-β信号的负调节剂。
