Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.
Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.
复制标题
DOI：
10.3389/fimmu.2020.575085
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Woodside DG
中科院分区：
文献类型：
--
作者：
Bakthavatsalam D;Craft JW Jr;Kazansky A;Nguyen N;Bae G;Caivano AR;Gundlach CW 4th;Aslam A;Ali S;Gupta S;Lin SY;Parthiban HD;Vanderslice P;Stephan CC;Woodside DG
白细胞炎症反应需要通过脾酪氨酸激酶（Syk）（一种直接结合整联蛋白β链胞质结构域的非受体激酶）进行整联蛋白细胞粘附分子信号传导。在这里，我们开发了一种高通量筛选，以确定Syk整合素胞质结构域相互作用的小分子抑制剂。筛选小分子化合物文库鉴定了β-内酰胺抗生素头孢磺啶和头孢他啶，其抑制整联蛋白β亚基胞质结构域与Syk串联SH 2结构域的结合（IC 50范围，1.02-4.9 µM）。建模表明拮抗剂在pITAM结合位点外与Syk结合。头孢他啶通过Syk抑制整合素信号传导，包括抑制白细胞介素-1 β和单核细胞趋化蛋白-1的粘附依赖性上调，但不抑制FcγRI信号传导介导的ITAM依赖性Syk磷酸化。我们的研究结果证明了一种新的手段，以靶向Syk独立于其激酶和pITAM结合位点，使整合素信号通过这种激酶被废除，但ITAM依赖性信号保持完整。由于通过Syk的整合素信号传导对于白细胞活化是必不可少的，这可能代表了靶向炎症的新方法。
Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin β-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the β-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin β-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02–4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1β and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation.
登录
查看更多内容
影响因子：
5.6
作者：
F端tterer, K;Wong, J;Waksman, G
通讯作者：
Waksman, G
影响因子：
2.7
作者：
Craft, JW;Legge, GB
通讯作者：
Legge, GB
影响因子：
--
作者：
Glickman, JF;Wu, X;Sills, M
通讯作者：
Sills, M
DOI：
10.1084/jem.186.7.1027
发表时间：
1997-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
14.8
作者：
Forli S;Huey R;Pique ME;Sanner MF;Goodsell DS;Olson AJ
通讯作者：
Olson AJ