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

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.