dlk1 specifically interacts with insulin-like growth factor binding protein 1 to modulate adipogenesis of 3T3-L1 cells
dlk1 specifically interacts with insulin-like growth factor binding protein 1 to modulate adipogenesis of 3T3-L1 cells
复制标题
DOI：
10.1016/j.jmb.2008.03.070
复制
发表时间：
2008-06-06
影响因子：
5.6
通讯作者：
Baladron, Victoriano
中科院分区：
文献类型：
--
作者：
Nueda, Maria-Luisa;Garcia-Ramirez, Jose Javier;Baladron, Victoriano
dlk 1是一种表皮生长因子（EGF）样同源异型蛋白，含有细胞内区域、单个跨膜结构域和具有六个EGF样重复序列和蛋白酶靶序列的细胞外区域。DLK 1作为脂肪形成和其它分化过程的调节剂发挥作用。dlk 1调控这些过程的分子机制尚不清楚。据报道，不同的Dlk 1 mRNA剪接变体，编码具有蛋白酶靶序列或不具有蛋白酶靶序列的同种型，决定膜相关或可溶性分泌的细胞外dlk 1蛋白的产生，这些蛋白似乎不同地影响3 T3-L1细胞的脂肪形成。特别是，只有可溶性变体抑制该过程。最近的一些证据表明，dlk 1可以调节细胞外刺激诱导分化。因此，在BALB/c 3 T3细胞中Dlk 1表达的强制性降低，这导致其响应于胰岛素样生长因子1（IGF-1）的脂肪形成潜力的增加，改变了由其触发的ERK 1/2活化的动力学和水平。我们鉴定了蛋白酶靶dlk 1区和IGF结合蛋白1（IGFBP 1）的非IGF结合区之间的强而特异的相互作用，一种与胰岛素样生长因子结合并调节其作用的蛋白质。我们还观察到，通过用反义Dlk 1表达构建体转染减少Dlk 1表达所引起的3 T3-L1细胞成脂潜能的增加被分化培养基中IGFBP 1的存在抑制。另一方面，培养基中IGFBP 1的存在略微增加了对照3 T3-L1细胞的成脂潜力，表达常规水平的Dlk 1。这些数据表明，膜dlk 1变体与细胞外IGFBP 1/IGF-1复合物结合，这可能有利于IGF-1的释放，并增加局部游离IGF-1浓度，从而增强IGF受体信号传导，导致脂肪形成。(c)2008爱思唯尔有限公司保留所有权利。
dlk1 is an epidermal growth factor (EGF)-like homeotic protein containing an intracellular region, a single transmembrane domain, and an extracellular region possessing six EGF-like repeats and a protease-target sequence. dlk1 functions as a modulator of adipogenesis, and other differentiation processes. The molecular mechanisms by which dlk1 regulates these processes are unclear. It has been reported that different Dlk1 mRNA spliced variants, encoding for isoforms possessing the protease-target sequence or not, determine the production of membrane-associated or soluble, secreted extracellular dlk1 proteins that appear to affect adipogenesis of 3T3-L1 cells differently. In particular, only soluble variants inhibit this process. Some recent evidence suggest that dlk1 may modulate extracellular stimuli inducing differentiation. Thus, an enforced decrease of Dlk1 expression in BALB/c 3T3 cells, which results in an increase of their adipogenic potential in response to insulin-like growth factor 1 (IGF-1), modifies the kinetics and levels of activation of ERK1/2 triggered by it. In this work, we identified a strong and specific interaction between the protease-target dlk1 region and the non-IGF binding region of IGF binding protein 1 (IGFBP1), a protein that binds to IGFs and modulates their action. We also observed that the increased adipogenic potential of 3T3-L1 cells caused by diminishing Dlk1 expression through transfection with an antisense Dlk1 expression construct was inhibited by the presence of IGFBP1 in the differentiation medium. On the other hand, the presence of IGFBP1 in the culture medium slightly increased the adipogenic potential of control 3T3-L1 cells, expressing regular levels of Dlk1. These data suggest that membrane dlk1 variants bind to extracellular IGFBP1/IGF-1 complexes, which may favor the release of IGF-1 and increase the local concentration of free IGF-1 that can enhance IGF receptor signaling, leading to adipogenesis. (c) 2008 Elsevier Ltd. All rights reserved.