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However, the emergence of SYK predates the advent of adaptive immunity, and its original functions independent of the adaptive immune system remain largely unknown. In this study, we identified and characterized a SYK homolog (bjSYK) in the amphioxus Branchiostoma japonicum, a key model for understanding immune system evolution. Phylogenetic analysis positioned bjSYK basally among deuterostome SYK kinases. Expression analysis revealed its localization in immune-relevant tissues. Contrary to the canonical activating role in vertebrates, functional studies demonstrated that bjSYK acts as a potent suppressor of nuclear factor-kappa B (NF-\u03baB) activation. Specifically, bjSYK directly interacts with bjMyD88 via its SH2 domains binding to a conserved hemi-ITAM motif, suppressing K63-linked polyubiquitination of bjMyD88 and consequently inhibiting bjMyD88-dependent NF-\u03baB signaling. Furthermore, bjSYK also suppresses NF-\u03baB activation through bjTRAF6, a key adaptor downstream of bjMyD88, by inhibiting its ubiquitination. These findings reveal an evolutionarily ancient inhibitory role of bjSYK in NF-\u03baB signaling in basal chordate innate immunity, suggesting that SYK-mediated negative regulation of Toll-like receptor pathways originates in amphioxus and provides a foundation for the context-dependent functions of SYK in vertebrate immunity.<\/jats:p>","DOI":"10.1093\/jmcb\/mjag009","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T12:41:25Z","timestamp":1773578485000},"source":"Crossref","is-referenced-by-count":0,"title":["Amphioxus tyrosine kinase SYK inhibits NF-\n                    <b>\u03ba<\/b>\n                    B activation through MyD88-dependent mechanism"],"prefix":"10.1093","volume":"18","author":[{"given":"Jie","family":"Xu","sequence":"first","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haikun","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyi","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuzhu","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , Shanghai 200240 ,","place":["China"]},{"name":"Sheng Yushou Center of Cell Biology and Immunology, Shanghai Jiao Tong University , Shanghai 200240 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangrui","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1419-3494","authenticated-orcid":false,"given":"Anlong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine , Beijing 102488 ,","place":["China"]},{"name":"Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou 510275 ,","place":["China"]},{"name":"Biomedical Research & Development Center, Sun Yat-sen University Institute of Advanced Studies Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"2026070309212305000_bib1","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.str.2024.09.024","article-title":"The mechanism of allosteric activation of SYK kinase derived from multiple phospho-ITAM-bound structures","volume":"32","author":"Bradshaw","year":"2024","journal-title":"Structure"},{"key":"2026070309212305000_bib2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s13059-022-02808-6","article-title":"Parallel evolution of amphioxus and vertebrate small-scale gene duplications","volume":"23","author":"Bras\u00f3-Vives","year":"2022","journal-title":"Genome Biol."},{"key":"2026070309212305000_bib3","first-page":"1253","article-title":"Identification of a gene encoding a novel protein-tyrosine kinase containing SH2 domains and ankyrin-like repeats","volume":"9","author":"Chan","year":"1994","journal-title":"Oncogene"},{"key":"2026070309212305000_bib4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s43188-024-00236-1","article-title":"Lysine-63-linked polyubiquitination: a principal target of cadmium carcinogenesis","volume":"40","author":"Chargui","year":"2024","journal-title":"Toxicol. 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