Abstract
RFWD2, an E3 ubiquitin ligase, is overexpressed in numerous human cancers, including leukemia, lung cancer, breast cancer, renal cell carcinoma, and colorectal cancer. The roles of RFWD2 in cancer are related to the targeting of its substrates for ubiquitination and degradation. This study aimed to investigate the role of TRIB2 in relation to the regulation of protein degradation through RFWD2. inBio Discover™ results demonstrated that TRIB2 can perform its functions by interacting with RFWD2 or other factors. TRIB2 can interact with and regulate RFWD2, which further attends the proteasome-mediated degradation of the RFWD2 substrate p-IκB-α. TRIB2 colocalizes with RFWD2-related IκB-α to form a ternary complex and further affects the IκB-α degradation by regulating its phosphorylation. Specific domain analysis showed that TRIB2 may bind to RFWD2 via its C-terminus, whereas it binds to IκB via its pseudokinase domain. TRIB2 acts as an oncogene and promotes cancer cell proliferation and migration, whereas RFWD2 knockdown reversed the role of TRIB2 in promoting cancer cell growth and colony formation in vitro and in vivo. In summary, this study reveals that TRIB2 promotes the progression of cancer by affecting the proteasome-mediated degradation of proteins through the interaction with RFWD2.
Highlights
The ubiquitin (Ub) proteasome system plays important roles in regulating the cell cycle, cell proliferation, cell migration, and apoptosis by affecting the levels and activities of biological function-related proteins [1, 2]
We further used eukaryotic expressed and purified TRIB2 and IkB-a proteins in coimmunoprecipitation experiments and observed that IkB-a antibodies may precipitate IkB-a and TRIB2 (Figure 3D). These results indicate that TRIB2, IkB-a, and RFWD2 form a ternary complex with RFWD2 though direct physical interactions, which may be related to the effect of TRIB2 on the proteasome-mediated degradation of proteins with RFWD2
The current study further verified whether the oncogenic role of TRIB2 depends on RFWD2 in regulating lung cancer cell proliferation
Summary
The ubiquitin (Ub) proteasome system plays important roles in regulating the cell cycle, cell proliferation, cell migration, and apoptosis by affecting the levels and activities of biological function-related proteins [1, 2]. Substrate proteins are attached with a small and highly conserved Ub protein consisting of 76 amino acids [3]. This attachment reaction is catalyzed by E1 Ub-activating enzyme, E2 Ub-conjugating enzyme, and E3 Ub-ligases [4]. The polyubiquitinated proteins are degraded timely by the Ub proteasome system [5], which is essential for maintaining cellular activity and homeostasis. E3 Ub ligases can recognize and interact with ubiquity late protein substrates [7], which in several cases lead to the upregulation of oncogenic activities and downregulation of tumor-suppressor activities [8]
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