LAUSR

Blocking MLK4-mediated IL-17RB phosphorylation diminishes downstream signaling and suppresses pancreatic cancer progression and metastasis. A “loop”-hole for pancreatic cancer treatment Tumor cells exploit signaling pathways involved in cell survival, proliferation, and migration to promote tumor growth and metastasis. Here, Wu et al. investigated one such pathway, interleukin-17 receptor B (IL-17RB) signaling, in the context of pancreatic cancer. The authors found that IL-17RB signaling in human pancreatic cancer specimens was associated with poorer outcomes, but signaling could be blocked in vitro using a peptide derived from the loop region of IL-17B, the ligand for IL-17RB. Further, IL-17B loop peptide treatment controlled tumor burden and extended survival in two mouse models of pancreatic cancer. These findings suggest that IL-17B loop peptide may be a therapeutic option for pancreatic cancer. The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.