P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions
Abstract P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigat...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-01720-w |
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| author | Elpida Tsonou Julia Y. Chu Polly A. Machin Anna G. Roberts Anne Segonds-Pichon David Baker David C. Hornigold Heidi C. E. Welch |
| author_facet | Elpida Tsonou Julia Y. Chu Polly A. Machin Anna G. Roberts Anne Segonds-Pichon David Baker David C. Hornigold Heidi C. E. Welch |
| author_sort | Elpida Tsonou |
| collection | DOAJ |
| description | Abstract P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigated the roles of P-Rex2 in glucose homeostasis using Prex2 –/– and catalytically-inactive Prex2 GD mice. We show that P-Rex2 is required for insulin sensitivity but limits glucose clearance, suppressing glucose uptake into liver and skeletal muscle independently of its catalytic activity. In hepatocytes, P-Rex2 suppresses Glut2 cell surface levels, mitochondrial membrane potential and mitochondrial ATP production. We identify the orphan GPCR Gpr21 as a P-Rex2 target and propose that P-Rex2 limits hepatic glucose clearance by controlling Gpr21 trafficking. In skeletal muscle cells, P-Rex2 suppresses glucose uptake through a separate adaptor function, independently of Gpr21. Additionally, P-Rex2 suppresses insulin secretion by pancreatic islets and plasma insulin levels. Finally, P-Rex2 plays distinct Rac-GEF activity dependent and independent roles in PIP3 production in liver and skeletal muscle, respectively. Together, our study identifies complex roles of P-Rex2 in glucose homeostasis, mediated through largely GEF-activity independent mechanisms which include the GPCR Gpr21 in hepatocytes and but are not obviously linked to the regulation of Pten. |
| format | Article |
| id | doaj-art-ab16cfac745e4ed485345eaade9808f0 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ab16cfac745e4ed485345eaade9808f02025-08-20T03:45:48ZengNature PortfolioScientific Reports2045-23222025-08-0115112210.1038/s41598-025-01720-wP-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functionsElpida Tsonou0Julia Y. Chu1Polly A. Machin2Anna G. Roberts3Anne Segonds-Pichon4David Baker5David C. Hornigold6Heidi C. E. Welch7Signalling Programme, The Babraham InstituteSignalling Programme, The Babraham InstituteSignalling Programme, The Babraham InstituteSignalling Programme, The Babraham InstituteBioinformatics Facility, The Babraham InstituteBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaSignalling Programme, The Babraham InstituteAbstract P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigated the roles of P-Rex2 in glucose homeostasis using Prex2 –/– and catalytically-inactive Prex2 GD mice. We show that P-Rex2 is required for insulin sensitivity but limits glucose clearance, suppressing glucose uptake into liver and skeletal muscle independently of its catalytic activity. In hepatocytes, P-Rex2 suppresses Glut2 cell surface levels, mitochondrial membrane potential and mitochondrial ATP production. We identify the orphan GPCR Gpr21 as a P-Rex2 target and propose that P-Rex2 limits hepatic glucose clearance by controlling Gpr21 trafficking. In skeletal muscle cells, P-Rex2 suppresses glucose uptake through a separate adaptor function, independently of Gpr21. Additionally, P-Rex2 suppresses insulin secretion by pancreatic islets and plasma insulin levels. Finally, P-Rex2 plays distinct Rac-GEF activity dependent and independent roles in PIP3 production in liver and skeletal muscle, respectively. Together, our study identifies complex roles of P-Rex2 in glucose homeostasis, mediated through largely GEF-activity independent mechanisms which include the GPCR Gpr21 in hepatocytes and but are not obviously linked to the regulation of Pten.https://doi.org/10.1038/s41598-025-01720-wP-Rex2P-Rex1Guanine-nucleotide exchange factor (GEF)Glucose homeostasisLiverSkeletal muscle |
| spellingShingle | Elpida Tsonou Julia Y. Chu Polly A. Machin Anna G. Roberts Anne Segonds-Pichon David Baker David C. Hornigold Heidi C. E. Welch P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions Scientific Reports P-Rex2 P-Rex1 Guanine-nucleotide exchange factor (GEF) Glucose homeostasis Liver Skeletal muscle |
| title | P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| title_full | P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| title_fullStr | P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| title_full_unstemmed | P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| title_short | P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| title_sort | p rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions |
| topic | P-Rex2 P-Rex1 Guanine-nucleotide exchange factor (GEF) Glucose homeostasis Liver Skeletal muscle |
| url | https://doi.org/10.1038/s41598-025-01720-w |
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