Department of Medicine, Allergy & Inflammation Program, University of Washington School of Medicine, Seattle, Washington 98109, USA.
J Biol Chem. 2010 Apr 23;285(17):12925-34. doi: 10.1074/jbc.M109.061754. Epub 2010 Feb 18.
Insulin-like growth factor-binding protein-5 (IGFBP-5) has IGF-1-independent intranuclear effects that are poorly defined. Treatment of cells with IGFBP-5 induces migration, prevents apoptosis, and leads to increased laminin subunit transcription. Similarly, filamin A (FLNa), an actin-binding protein that participates in cell attachment, plays important additional roles in signal transduction and modulation of transcriptional responses. In this report, we show that IGFBP-5 leads to dephosphorylation of FLNa with subsequent FLNa cleavage. Following cleavage, there is enhanced recruitment of Smad3/4 to a C-terminal FLNa fragment with nuclear translocation and subsequent binding to the promoter region of the laminin gamma1 (lamc1) gene. FLNa knockdown prevents IGFBP-5-mediated increases in lamc1 transcription. These data indicate that IGFBP-5 induces formation of a FLNa-based nuclear shuttle that recruits transcription factors and regulates transcription of IGFBP-5 target genes. These studies provide new insights into the mechanisms whereby IGFBP-5 and FLNa exert intranuclear effects.
胰岛素样生长因子结合蛋白-5（IGFBP-5）具有 IGF-1 非依赖性的核内效应，但这些效应的定义还不明确。用 IGFBP-5 处理细胞会诱导细胞迁移、防止细胞凋亡，并导致层粘连蛋白亚基转录增加。同样，作为一种参与细胞附着的肌动蛋白结合蛋白的细丝蛋白 A（FLNa），在信号转导和转录反应的调节中也发挥着重要的额外作用。在本报告中，我们表明 IGFBP-5 导致 FLNa 的去磷酸化，随后 FLNa 发生切割。切割后，Smad3/4 被招募到 FLNa 的 C 端片段，该片段发生核转位，并随后与层粘连蛋白 γ1（lamc1）基因的启动子区域结合。FLNa 的敲低可阻止 IGFBP-5 介导的 lamc1 转录增加。这些数据表明，IGFBP-5 诱导形成了一种基于 FLNa 的核穿梭物，该穿梭物可募集转录因子并调节 IGFBP-5 靶基因的转录。这些研究为 IGFBP-5 和 FLNa 发挥核内效应的机制提供了新的见解。
