CXCL17 activates three MAS-related G protein-coupled receptors independently of its conserved C-terminal fragment

** The preprint operates within the established paradigm of G protein-coupled receptor (GPCR) signaling in immunology and chemotaxis. Specifically, it focuses on understanding the receptor targets and activation mechanisms of CXCL17, a chemokine with a debated receptor.

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This research falls primarily under "Normal Science" because it uses accepted methods (NanoBiT assays, chemotaxis assays) to investigate a specific question within the existing GPCR paradigm. It seeks to refine our understanding of CXCL17 signaling, which is a puzzle within the established framework.

However, I also classify it as "Model Drift" due to the preprint's findings challenging the prior understanding of CXCL17's receptor interactions. The study confirms MRGPRX2 activation by CXCL17 but also shows activation of other MRGPRs (MRGPRX1, MAS1) *and* demonstrates that CXCL17's conserved C-terminal fragment – crucial for GPR25 activation – isn't necessary for MRGPR activation. These findings point to unexpected complexities in CXCL17 signaling, highlighting potential limitations or nuances within the current understanding of chemokine-receptor interactions. This might be a starting point for future research that could lead to a more nuanced model of CXCL17 function. While not a full-blown crisis, the findings introduce enough unexpected behavior to suggest a potential drift away from a simplistic model of CXCL17 receptor specificity.