{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:28:57Z","timestamp":1785432537758,"version":"3.56.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"30","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173841"],"award-info":[{"award-number":["82173841"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273777"],"award-info":[{"award-number":["82273777"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:p>\n                    \u03b1-fluoro-\u03b2-alanine (FBAL), a catabolite of the chemotherapeutic agent 5-fluorouracil (5-FU), has attracted significant attention due to its cardiotoxicity and neurotoxicity. However, its association with 5-FU resistance, a major obstacle in cancer treatment, has rarely been reported. In this study, FBAL was identified as a \u03b2-arrestin1-biased ligand of sphingosine 1-phosphate receptor 2 (S1PR2), which upregulates dihydropyrimidine dehydrogenase (DPD) expression and drives 5-FU resistance in colorectal cancer. Mechanistically, following exposure to FBAL, S1PR2, a G protein\u2013coupled receptor (GPCR), is phosphorylated by recruiting G protein\u2013coupled receptor kinase 6 (GRK6). Phosphorylated S1PR2 coupled with \u03b2-arrestin1, but not G proteins, to activate the MEK\/ERK\/AP-1 pathway and promote\n                    <jats:italic toggle=\"yes\">DPYD<\/jats:italic>\n                    transcription. Ser343 was identified as the key phosphorylation site of S1PR2 using IP-MS analysis. This residue within the C-terminal domain mediates receptor interaction with \u03b2-arrestin-1 to activate the \u03b2-arrestin-1-dependent ERK pathway, as was confirmed in HCT116\n                    <jats:sup>S1PR2KO-\u0394C<\/jats:sup>\n                    cells and HCT116\n                    <jats:sup>S1PR2KO-S343A<\/jats:sup>\n                    cells.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    , mice bearing orthotopic xenografts of HCT116\n                    <jats:sup>S1PR2KO-S343A<\/jats:sup>\n                    cells exhibited significantly enhanced higher sensitivity to 5-FU treatment compared to those HCT116\n                    <jats:sup>S1PR2KO-WT<\/jats:sup>\n                    cells following FBAL. Taken together, this study showed that exposure to FBAL induces S1PR2 phosphorylation at Ser343 within the C-terminal mediated by GRK6, activating the \u03b2-arrestin1-dependent ERK pathway to upregulate DPD expression. This study not only delineates a phosphorylation-dependent signaling pathway in chemoresistance but also establishes S1PR2 as a promising therapeutic target for overcoming 5-FU resistance in cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2533427123","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T19:15:07Z","timestamp":1784574907000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["\u03b1-fluoro-\u03b2-alanine functions as a \u03b2-arrestin1-biased ligand of S1PR2 to upregulate DPD expression in cancer cells"],"prefix":"10.1073","volume":"123","author":[{"given":"Mingyong","family":"Tan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}],"name":"Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University","place":["Beijing, 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