The membrane-associated adaptor protein DOK5 is upregulated in systemic sclerosis and associated with IGFBP-5-induced fibrosis.
The membrane-associated adaptor protein DOK5 is upregulated in systemic sclerosis and associated with IGFBP-5-induced fibrosis.
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DOI：
10.1371/journal.pone.0087754
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Feghali-Bostwick CA
中科院分区：
文献类型：
--
作者：
Yasuoka H;Yamaguchi Y;Feghali-Bostwick CA
系统性硬化症（SSc）的特征在于由于成纤维细胞增殖和细胞外基质（ECM）的过度产生而导致的皮肤和内脏器官的过度纤维化。我们已经表明，胰岛素样生长因子结合蛋白（IGFBP）-5在体外，离体和体内纤维化的发展中起着重要作用。我们使用表达IGFBP-5的原代成纤维细胞的基因表达谱鉴定了酪氨酸激酶/对接蛋白（DOK）5下游的膜相关衔接蛋白作为IGFBP-5调节的靶基因。DOK 5是与细胞内信号传导相关的酪氨酸激酶底物。我们的目的是确定DOK 5在SSc发病机制中的作用，特别是在IGFBP-5诱导的纤维化中的作用。在体外，内源性和外源性IGFBP-5在原代人成纤维细胞中增加DOK 5 mRNA和蛋白水平。DOK 5上调需要丝裂原活化蛋白激酶（MAPK）信号级联的激活。此外，IGFBP-5触发DOK 5的核转位。DOK 5蛋白水平在小鼠皮肤和肺中也被IGFBP-5体内增加。为了确定DOK 5对纤维化的作用，在器官培养物中在人皮肤中离体表达DOK 5。DOK 5在人皮肤中的表达导致真皮厚度的显著增加。最后，比较了SSc患者和健康供体的原代成纤维细胞和肺组织中DOK 5的水平。与健康对照组相比，SSc患者的成纤维细胞和皮肤组织以及SSc患者的肺组织中DOK 5 mRNA和蛋白水平均显著升高。我们的研究结果表明，IGFBP-5诱导其促纤维化作用，至少部分，通过DOK 5。此外，IGFBP-5和DOK 5在SSc成纤维细胞和组织中均增加，因此可能共同促进纤维化。
Systemic sclerosis (SSc) is characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (ECM). We have shown that insulin-like growth factor binding protein (IGFBP)-5 plays an important role in the development of fibrosis in vitro, ex vivo, and in vivo. We identified a membrane-associated adaptor protein, downstream of tyrosine kinase/docking protein (DOK)5, as an IGFBP-5-regulated target gene using gene expression profiling of primary fibroblasts expressing IGFBP-5. DOK5 is a tyrosine kinase substrate associated with intracellular signaling. Our objective was to determine the role of DOK5 in the pathogenesis of SSc and specifically in IGFBP-5-induced fibrosis. DOK5 mRNA and protein levels were increased in vitro by endogenous and exogenous IGFBP-5 in primary human fibroblasts. DOK5 upregulation required activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Further, IGFBP-5 triggered nuclear translocation of DOK5. DOK5 protein levels were also increased in vivo in mouse skin and lung by IGFBP-5. To determine the effect of DOK5 on fibrosis, DOK5 was expressed ex vivo in human skin in organ culture. Expression of DOK5 in human skin resulted in a significant increase in dermal thickness. Lastly, levels of DOK5 were compared in primary fibroblasts and lung tissues of patients with SSc and healthy donors. Both DOK5 mRNA and protein levels were significantly increased in fibroblasts and skin tissues of patients with SSc compared with those of healthy controls, as well as in lung tissues of SSc patients. Our findings suggest that IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. Furthermore, IGFBP-5 and DOK5 are both increased in SSc fibroblasts and tissues and may thus be acting in concert to promote fibrosis.
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DOI：
10.2174/1874312900802010017
发表时间：
2008
期刊：
The open rheumatology journal
影响因子：
--
作者：
Yasuoka H;Larregina AT;Yamaguchi Y;Feghali-Bostwick CA
通讯作者：
Feghali-Bostwick CA
影响因子：
6
作者：
Pilewski, JM;Liu, LX;Feghali-Bostwick, CA
通讯作者：
Feghali-Bostwick, CA
影响因子：
17.1
作者：
Yamaguchi Y;Takihara T;Chambers RA;Veraldi KL;Larregina AT;Feghali-Bostwick CA
通讯作者：
Feghali-Bostwick CA
影响因子：
5
作者：
Hetzel, M;Bachem, M;Faehling, M
通讯作者：
Faehling, M
影响因子：
--
作者：
Brissett, Monique;Veraldi, Kristen L.;Pilewski, Joseph M.;Medsger, Thomas A., Jr.;Feghali-Bostwick, Carol A.
通讯作者：
Feghali-Bostwick, Carol A.