Tyr42 phosphorylation of RhoA GTPase promotes tumorigenesis through nuclear factor (NF)-κB
| Autor: | Kyoung-Chan Choi, Yong-Sun Kim, Hwee-Seon Park, Chang-Won Hong, Eun-Kyoung Choi, Jae-Gyu Kim, Jae-Bong Park |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
VAV2 RHOA Carcinoma Hepatocellular Carcinogenesis Breast Neoplasms IκB kinase Biochemistry 03 medical and health sciences Mice 0302 clinical medicine Physiology (medical) Cell Line Tumor Animals Humans Phosphorylation Protein kinase C Mice Inbred BALB C biology Chemistry Liver Neoplasms NF-kappa B Hydrogen Peroxide Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology HEK293 Cells RAW 264.7 Cells 030220 oncology & carcinogenesis Cancer research biology.protein Tyrosine Female Guanine nucleotide exchange factor rhoA GTP-Binding Protein Tyrosine kinase HT29 Cells Protein Processing Post-Translational Neoplasm Transplantation Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | Free radical biologymedicine. 112 |
| ISSN: | 1873-4596 |
| Popis: | Dysregulation of reactive oxygen species (ROS) levels is implicated in the pathogenesis of several diseases, including cancer. However, the molecular mechanisms for ROS in tumorigenesis have not been well established. In this study, hydrogen peroxide activated nuclear factor-κB (NF-κB) and RhoA GTPase. In particular, we found that hydrogen peroxide lead to phosphorylation of RhoA at Tyr42 via tyrosine kinase Src. Phospho-Tyr42 (p-Tyr42) residue of RhoA is a binding site for Vav2, a guanine nucleotide exchange factor (GEF), which then activates p-Tyr42 form of RhoA. P-Tyr42 RhoA then binds to IκB kinase γ (IKKγ), leading to IKKβ activation. Furthermore, RhoA WT and phospho-mimic RhoA, RhoA Y42E, both promoted tumorigenesis, whereas the dephospho-mimic RhoA, RhoA Y42F suppressed it. In addition, hydrogen peroxide induced NF-κB activation and cell proliferation, along with expression of c-Myc and cyclin D1 in the presence of RhoA WT and RhoA Y42E, but not RhoA Y42F. Indeed, levels of p-Tyr42 Rho, p-Src, and p-65 are significantly increased in human breast cancer tissues and show correlations between each of the two components. Conclusively, the posttranslational modification of as RhoA p-Tyr42 may be essential for promoting tumorigenesis in response to generation of ROS. |
| Databáze: | OpenAIRE |
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