Academic Journal
The regulation of organic anion transporting polypeptide 1B1 by nonreceptor tyrosine kinase YES1.
| Τίτλος: | The regulation of organic anion transporting polypeptide 1B1 by nonreceptor tyrosine kinase YES1. |
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| Συγγραφείς: | Wang X; Guangdong Laboratory for Lingnan Modern Agriculture, College of Life Sciences, South China Agricultural University, Guangzhou, China., Li Z; Guangdong Laboratory for Lingnan Modern Agriculture, College of Life Sciences, South China Agricultural University, Guangzhou, China., Tang L; Guangdong Laboratory for Lingnan Modern Agriculture, College of Life Sciences, South China Agricultural University, Guangzhou, China., Hong M; Guangdong Laboratory for Lingnan Modern Agriculture, College of Life Sciences, South China Agricultural University, Guangzhou, China; Guangdong Provincial Key Laboratory for the Development Biology and Environmental Adaptation of Agricultural Organisms, South China Agricultural University, Guangzhou, China. Electronic address: mh2788@scau.edu.cn. |
| Πηγή: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2025 Dec; Vol. 53 (12), pp. 100194. Date of Electronic Publication: 2025 Nov 01. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2025- : [Amsterdam] : Elsevier Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| Ιατρικοί όροι (MeSH): | Liver-Specific Organic Anion Transporter 1*/metabolism , Proto-Oncogene Proteins c-yes*/metabolism , Proto-Oncogene Proteins c-yes*/genetics, Phosphorylation/drug effects ; Caveolin 1/metabolism ; src-Family Kinases/metabolism ; src-Family Kinases/antagonists & inhibitors ; Indoles/pharmacology ; Humans ; Proto-Oncogene Mas ; HEK293 Cells ; Biological Transport |
| Περίληψη: | Organic anion transporting polypeptide 1B1 (OATP1B1), the hepatic-specific uptake transporter, plays key roles in the absorption, distribution, and excretion of a broad range of endogenous and exogenous compounds. Altered expression and function of OATP1B1 affect the bioavailability and pharmacokinetics of various clinically important drugs. In this study, OATP1B1 uptake function was found to be significantly suppressed by SRC proto-oncogene, non-receptor tyrosine kinase family kinase inhibitors, with SU6656 demonstrating the most potent inhibitory effect. Knockdown and overexpression experiments revealed that YES1 is the specific SRC proto-oncogene, non-receptor tyrosine kinase family kinase responsible for regulating OATP1B1. Further, YES1 was found to interact with OATP1B1, and the tyrosine phosphorylation status of the transporter was suppressed by both the SU6656 treatment and the knockdown of the tyrosine kinase. Moreover, Caveolin 1 (CAV-1), the oligomeric scaffolding protein, was found to interact with OATP1B1. CAV-1 knockdown significantly suppressed the uptake function of OATP1B1. Although the reduction of CAV-1 did not affect the interaction between YES-1 and the transporter, it affected the phosphorylation level of OATP1B1. Immunofluorescence analysis indicated that CAV-1 colocalized with OATP1B1, and the disruption of lipid rafts significantly reduced the association of CAV-1 with OATP1B1, suggesting that the integrity of lipid rafts is essential for the effect of CAV-1 on OATP1B1. In conclusion, YES1 was identified as a regulator for OATP1B1. The tyrosine kinase physically interacts with OATP1B1, and the conformation that facilitates the phosphorylation of OATP1B1 by YES1 is likely maintained by CAV-1. SIGNIFICANCE STATEMENT: The present study found that YES-1 regulates the function of organic anion transporting polypeptide 1B1 (OATP1B1) by interacting with the transporter and influencing its tyrosine phosphorylation status. Caveolin-1 was shown to interact with OATP1B1 as well. Abrogation of Caveolin-1 exhibited no effect on the interaction between YES-1 and OATP1B1 but reduced the phosphorylation level of the transporter. Taken together, inhibitors of YES-1 may alter the uptake function of OATP1B1, potentially leading to drug-drug interactions related to post-translational modification. (Copyright © 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Conflict of interest The authors declare no conflicts of interest. |
| Contributed Indexing: | Keywords: Caveolin-1; OATP1B1; Phosphorylation; Protein-protein interaction; Regulatory mechanism; YES1 |
| Substance Nomenclature: | 0 (Liver-Specific Organic Anion Transporter 1) 0 (Proto-Oncogene Mas) 0 (MAS1 protein, human) 0 (SLCO1B1 protein, human) EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) 0 (Caveolin 1) EC 2.7.10.2 (YES1 protein, human) EC 2.7.10.2 (src-Family Kinases) 0 (Indoles) |
| Entry Date(s): | Date Created: 20251126 Date Completed: 20251228 Latest Revision: 20251228 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.dmd.2025.100194 |
| PMID: | 41297177 |
| Βάση Δεδομένων: | MEDLINE |
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