{"doi":"10.3390/cells12070980","title":"S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720","abstract":"Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination. Compared to luminal breast cancer cells, TNBC cells exhibit a significant increase of phospho-S1P1 T236 but not the total S1P1 levels. Misexpression of phosphorylation-defective S1P1 T236A (alanine) decreases TNBC cell migration in vitro and disease invasion in zebrafish xenografts. Pharmacologic disruption of S1P1 T236 phosphorylation, using either a pan-AKT inhibitor (MK2206) or an S1P1 functional antagonist (FTY720, an FDA-approved drug for treating multiple sclerosis), suppresses TNBC cell migration in vitro and tumor invasion in vivo. Finally, we show that human TNBC cells with AKT activation and elevated phospho-S1P1 T236 are sensitive to FTY720-induced cytotoxic effects. These findings indicate that the AKT-enhanced phosphorylation of S1P1 T236 mediates much of the TNBC invasiveness, providing a potential biomarker to select TNBC patients for the clinical application of FTY720.","journal":"Cells","year":2023,"id":358315,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337294,"name":"Sheng Li","orcid":"0000-0003-4070-7345","position":1,"is_corresponding":false},{"id":399643,"name":"Ning Shen","orcid":"0000-0003-4709-3374","position":2,"is_corresponding":false},{"id":1108774,"name":"Soo Kyung Hwang","orcid":null,"position":3,"is_corresponding":false},{"id":1108775,"name":"Gina Nguyen","orcid":null,"position":4,"is_corresponding":false},{"id":1108776,"name":"Wenling Yu","orcid":null,"position":5,"is_corresponding":false},{"id":399640,"name":"Chen Khuan Wong","orcid":"0000-0001-9811-3334","position":6,"is_corresponding":false},{"id":559977,"name":"Ryan J. Quinton","orcid":null,"position":7,"is_corresponding":false},{"id":632077,"name":"Jason N. Berman","orcid":"0000-0002-4053-6067","position":8,"is_corresponding":false},{"id":22056,"name":"Ching‐Ti Liu","orcid":"0000-0002-0703-0742","position":9,"is_corresponding":false},{"id":1025137,"name":"Anurag Singh","orcid":"0000-0003-4705-8683","position":10,"is_corresponding":false},{"id":559318,"name":"Neil J. Ganem","orcid":"0000-0003-0269-6585","position":11,"is_corresponding":false},{"id":399646,"name":"Sam Thiagalingam","orcid":"0000-0001-5211-266X","position":12,"is_corresponding":false},{"id":262729,"name":"Hui Feng","orcid":"0000-0003-1318-821X","position":13,"is_corresponding":false},{"id":1108773,"name":"Fabrice Laroche","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:13:43.629667Z","pmid":"37048053","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}