Wu, Heng-HsiungHeng-HsiungWuTsai, Lung-HungLung-HungTsaiHuang, Chun-KaiChun-KaiHuangHsu, Pang-HungPang-HungHsuChen, Mei-YuMei-YuChenChen, Yi-IngYi-IngChenHu, Chun-MeiChun-MeiHuShen, Chia-NingChia-NingShenLee, Chen-ChenChen-ChenLeeMING-CHU CHANGYU-TING CHANGYU-WEN TIENYUNG-MING JENGLee, Eva Y-H PEva Y-H PLeeLee, Wen-HwaWen-HwaLee2022-09-142022-09-142021-03-031946-6234https://scholars.lib.ntu.edu.tw/handle/123456789/620168The 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.enINTERLEUKIN 17 RECEPTOR; NEURO-INSULAR NETWORK; LIGAND-BINDING SITE; CUTTING EDGE; PROTEIN; IDENTIFICATION; DOMAIN; SEFIR; UBIQUITINATION; TRANSDUCTION[SDGs]SDG3journal article10.1126/scitranslmed.abc2823336583522-s2.0-85102311475WOS:000625385600005