{'fraction_non_alphanumeric': 0.024096385542168676, 'fraction_numerical': 0.020240963855421686, 'mean_word_length': 5.4875, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Mutations in Lyn Kinase Causes Changes in Neutrophil Function and Migration

The Src Family Kinase (SFK) Lyn plays important regulatory roles in immune cells including neutrophils. As a signaling protein, Lyn has been shown to regulate neutrophil migration and endothelial adhesion, contributing to inflammation. Lyn contains a tyrosine kinase domain as well as SH2 and SH3 domains allowing for adaptor functions. A set of patients with systemic neutrophil‐induced inflammation have been shown to have de novo germline mutations in Lyn, Y508* and Y508F, affecting the negative regulatory tyrosine residue of Lyn. The purpose of this study is to evaluate the physiological, cellular, and biochemical effects of this mutation, and further understand the role of Lyn Kinase in neutrophil function. Patients were found to have a gain‐of‐function mutation and presented with skin vasculitis that improved with administration of the SFK inhibitor, dasatinib. We generated stable expression lines of WT, Y508*, and Y508F pMX‐Lyn‐GFP in neutrophil‐like PLB‐985 cells. Kinase activity assays show increased phosphorylation of SFK substrate, SAM68, and overall tyrosine phosphorylation with both Y508*and Y508F expression compared to WT, indicating higher kinase activity in the mutants. Further experiments using kinase‐dead mutants indicate that the higher kinase activity is caused by increases in Lyn's kinase activity and not its adaptor function. In addition, we evaluated the chemotaxis of PLB‐985 cells towards the chemoattractant fmlp using transwell migration assays and microfluidic devices that allow for the generation of chemoattractant gradients. Y508* and Y508F PLB‐985 cells were found to have significantly increased chemotaxis towards 10 mM fmlp (p<0.05) than WT Lyn. Our data supports the role of Lyn as a positive regulator of migration, demonstrating that disruption in the regulatory domain of Lyn can cause cellular and physiological changes. Furthermore, it highlights the role of the de novo germline mutations in Lyn as a cause of human inflammatory disease.