Phosphorylation of PPDPF via IL6-JAK2 activates the Wnt/beta-catenin pathway in colorectal cancer

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to beta-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxy-methane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1 alpha (CK1 alpha), thereby disrupting its binding to Axin, disassociating the beta-catenin destruction complex, decreasing the phosphorylation of beta-catenin, and activating the Wnt/beta-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/beta-catenin signaling pathway, providing a potential novel therapeutic target.