BNIP-2 retards breast cancer cell migration by coupling microtubule-mediated GEF-H1 and RhoA activation
SCIENCE ADVANCES
Authors: Pan, Meng; Chew, Ti Weng; Wong, Darren Chen Pei; Xiao, Jingwei; Ong, Hui Ting; Chin, Jasmine Fei Li; Low, Boon Chuan
Abstract
Microtubules display dynamic turnover during cell migration, leading to cell contractility and focal adhesion maturation regulated by Rho guanosine triphosphatase activity. This interplay between microtubules and actomyosin is mediated by guanine nucleotide exchange factor (GEF)-H1 released after microtubule depolymerization or microtubule disconnection from focal adhesions. However, how GEF-H1 activates Rho upon microtubule disassembly remains elusive. Here, we found that BNIP-2, a BCH domain-containing protein that binds both RhoA and GEF-H1 and traffics with kinesin-1 on microtubules, is important for GEF-H1-driven RhoA activation upon microtubule disassembly. Depletion of BNIP-2 in MDA-MB-231 breast cancer cells decreases RhoA activity and promotes cell migration. Upon nocodazole-induced microtubule disassembly, the interaction between BNIP-2 and GEF-H1 increases, while knockdown of BNIP-2 reduces RhoA activation and cell rounding via uncoupling RhoA-GEF-H1 interaction. Together, these findings revealed that BNIP-2 couples microtubules and focal adhesions via scaffolding GEF-H1 and RhoA, fine-tuning RhoA activity and cell migration.
Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
ADVANCED SCIENCE
Authors: Sun, Zhongya; Zhang, Hao; Zhang, Yuanyuan; Liao, Liping; Zhou, Wen; Zhang, Fengcai; Lian, Fulin; Huang, Jing; Xu, Pan; Zhang, Rukang; Lu, Wenchao; Zhu, Mingrui; Tao, Hongru; Yang, Feng; Ding, Hong; Chen, Shijie; Yue, Liyan; Zhou, Bing; Zhang, Naixia; Tan, Minjia; Jiang, Hualiang; Chen, Kaixian; Liu, Bo; Liu, Chuanpeng; Dang, Yongjun; Luo, Cheng
Abstract
The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward "undruggable" protein targets.
COA
Publication 
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