RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells

Abstract

The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer.

Impaired erythropoietin‐producing hepatocellular B receptors signaling in the prefrontal cortex and hippocampus following maternal immune activation in male rats

“…52 Our model is a pregnancy infection model, which was found to have increased plasma inflammatory factors, including TNF-α, after viral infection and it has been reported that TNF-α activates the NF-κB pathway, which affects EphB2 transcription, all three of which can be increased under injury or disease states. 84,85 In Opcml-deficient mice, which exhibit schizophrenic-like behaviors but reduced EphB2 expression, 54 we differ from previous studies, haps because we use a different The pathogenetic mechanisms of different diseases may lead to different changes in EphB2 receptor expression. One limitation of this study is that we did not obtain insight into the mechanisms underlying these changes in the offspring following immune challenge.…”

“…Using a model of depression in mice induced by chronic social defeat stress shows a decrease in EphB2 receptor protein levels and an associated susceptibility to stress 52 . Our model is a pregnancy infection model, which was found to have increased plasma inflammatory factors, including TNF‐α, after viral infection and it has been reported that TNF‐α activates the NF‐κB pathway, which affects EphB2 transcription, all three of which can be increased under injury or disease states 84,85 . In Opcml‐deficient mice, which exhibit schizophrenic‐like behaviors but reduced EphB2 expression, 54 we differ from previous studies, haps because we use a different model.…”

Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets

“…Recently, a detailed description of the EPHB2-RNF186-TAB2-TAK1 signaling cascade in CRC carcinogenesis has been described in detail ( 137 ). Upon tumor necrosis factor (TNF) stimulation, EphB2 undergoes ubiquitination mediated by the E3 ligase RNF186, resulting in the recruitment and phosphorylation of TAB2.…”

“…The absence of RNF186 in CRC cells significantly reduces the malignant phenotype in a murine colitis model. Furthermore, a genetic mutation in EphB2 has been identified in a family with CRC, demonstrating a gain-of-function mutation that enhances TNF signaling activation ( 137 ).…”

Insights on the Biomarker Potential of Exosomal Non-Coding RNAs in Colorectal Cancer: An In Silico Characterization of Related Exosomal lncRNA/circRNA–miRNA–Target Axis

“…The literature review revealed that the vast majority of the identified genes had previously been linked to colorectal cancer pathogenesis. Of these genes, the ones that seem to have an important role in CRC are EZH2, PTEN, EGFR, IGF1, HGF, SMAD4 and PTGS2 [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ].…”