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- Publisher Website: 10.1073/pnas.2016997117
- Scopus: eid_2-s2.0-85096079704
- PMID: 33122440
- WOS: WOS:000590745300013
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Article: The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells
Title | The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells |
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Authors | |
Keywords | Glucose-stimulated insulin secretion Type 2 diabetes Rac1 F-actin depolymerization APPL2 |
Issue Date | 2020 |
Publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org |
Citation | Proceedings of the National Academy of Sciences, 2020, v. 117 n. 45, p. 28307-28315 How to Cite? |
Abstract | Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells. |
Persistent Identifier | http://hdl.handle.net/10722/294101 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Wang, B | - |
dc.contributor.author | Lin, H | - |
dc.contributor.author | Li, X | - |
dc.contributor.author | Lu, W | - |
dc.contributor.author | Kim, JB | - |
dc.contributor.author | Xu, A | - |
dc.contributor.author | Cheng, KKY | - |
dc.date.accessioned | 2020-11-23T08:26:20Z | - |
dc.date.available | 2020-11-23T08:26:20Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences, 2020, v. 117 n. 45, p. 28307-28315 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | http://hdl.handle.net/10722/294101 | - |
dc.description.abstract | Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells. | - |
dc.language | eng | - |
dc.publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org | - |
dc.relation.ispartof | Proceedings of the National Academy of Sciences | - |
dc.subject | Glucose-stimulated insulin secretion | - |
dc.subject | Type 2 diabetes | - |
dc.subject | Rac1 | - |
dc.subject | F-actin depolymerization | - |
dc.subject | APPL2 | - |
dc.title | The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells | - |
dc.type | Article | - |
dc.identifier.email | Wang, B: baile612@hku.hk | - |
dc.identifier.email | Xu, A: amxu@hkucc.hku.hk | - |
dc.identifier.authority | Wang, B=rp02797 | - |
dc.identifier.authority | Xu, A=rp00485 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1073/pnas.2016997117 | - |
dc.identifier.pmid | 33122440 | - |
dc.identifier.pmcid | PMC7668165 | - |
dc.identifier.scopus | eid_2-s2.0-85096079704 | - |
dc.identifier.hkuros | 319049 | - |
dc.identifier.hkuros | 315786 | - |
dc.identifier.volume | 117 | - |
dc.identifier.issue | 45 | - |
dc.identifier.spage | 28307 | - |
dc.identifier.epage | 28315 | - |
dc.identifier.isi | WOS:000590745300013 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 0027-8424 | - |