PHLPP1 regulates CFTR activity and lumen expansion through AMPK.
| Title: | PHLPP1 regulates CFTR activity and lumen expansion through AMPK. |
|---|---|
| Authors: | Lobert VH; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Skardal ML; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Malerød L; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Simensen JE; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Algra HA; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Andersen AN; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Fleischer T; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Enserink HA; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Liestøl K; Department of Informatics, University of Oslo, Oslo 0316, Norway.; Heath JK; Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.; Rusten TE; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.; Stenmark HA; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0379, Norway.; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo 0379, Norway. |
| Source: | Development (Cambridge, England) [Development] 2022 Oct 15; Vol. 149 (20). Date of Electronic Publication: 2022 Aug 23. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Company Of Biologists Limited Country of Publication: England NLM ID: 8701744 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9129 (Electronic) Linking ISSN: 09501991 NLM ISO Abbreviation: Development Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge Eng : Company Of Biologists Limited; Original Publication: [Cambridge] : Company of Biologists, [c1987- |
| MeSH Terms: | AMP-Activated Protein Kinases*/genetics ; AMP-Activated Protein Kinases*/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator*/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Animals ; Humans ; Phosphorylation |
| Abstract: | Complex organ development depends on single lumen formation and its expansion during tubulogenesis. This can be achieved by correct mitotic spindle orientation during cell division, combined with luminal fluid filling that generates hydrostatic pressure. Using a human 3D cell culture model, we have identified two regulators of these processes. We find that pleckstrin homology leucine-rich repeat protein phosphatase (PHLPP) 2 regulates mitotic spindle orientation, and thereby midbody positioning and maintenance of a single lumen. Silencing the sole PHLPP family phosphatase in Drosophila melanogaster, phlpp, resulted in defective spindle orientation in Drosophila neuroblasts. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) is the main channel regulating fluid transport in this system, stimulated by phosphorylation by protein kinase A and inhibited by the AMP-activated protein kinase AMPK. During lumen expansion, CFTR remains open through the action of PHLPP1, which stops activated AMPK from inhibiting ion transport through CFTR. In the absence of PHLPP1, the restraint on AMPK activity is lost and this tips the balance in the favour of channel closing, resulting in the lack of lumen expansion and accumulation of mucus.; (© 2022. Published by The Company of Biologists Ltd.) |
| Competing Interests: | Competing interests The authors declare no competing or financial interests. |
| References: | Methods Mol Biol. 2018;1817:41-46. (PMID: 29959701); Nat Med. 2013 Jul;19(7):939-45. (PMID: 23727931); EMBO Rep. 2014 Apr;15(4):428-37. (PMID: 24591568); Curr Biol. 2016 May 9;26(9):1248. (PMID: 27166686); Curr Opin Genet Dev. 2015 Jun;32:24-30. (PMID: 25698116); J Cell Biol. 2010 May 17;189(4):661-9. (PMID: 20479467); Am J Physiol Cell Physiol. 2003 May;284(5):C1297-308. (PMID: 12519745); Mol Cell. 2010 May 28;38(4):512-23. (PMID: 20513427); Dev Cell. 2011 Jul 19;21(1):102-19. (PMID: 21763612); J Biol Chem. 2003 Jan 10;278(2):998-1004. (PMID: 12427743); Science. 1989 Sep 8;245(4922):1066-73. (PMID: 2475911); Cell Logist. 2014 Jan 1;4(1):e28928. (PMID: 24843830); Curr Opin Cell Biol. 2016 Dec;43:1-6. (PMID: 27318429); Circ Res. 2007 Feb 16;100(3):328-41. (PMID: 17307971); J Cell Biol. 2008 Nov 17;183(4):625-33. (PMID: 19001128); Am J Physiol Cell Physiol. 2009 Jul;297(1):C94-101. (PMID: 19419994); J Virol. 1998 Nov;72(11):8463-71. (PMID: 9765382); J Biol Chem. 2003 Apr 25;278(17):14920-5. (PMID: 12594205); Development. 2013 Apr;140(8):1703-12. (PMID: 23487313); Commun Integr Biol. 2017 Jul 5;10(4):e1338990. (PMID: 28919938); J Biol Chem. 2009 Feb 27;284(9):5645-53. (PMID: 19095655); Commun Integr Biol. 2012 Sep 1;5(5):480-4. (PMID: 23181165); Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2462-7. (PMID: 21262823); Mol Cell. 2007 Mar 23;25(6):917-31. (PMID: 17386267); Mol Cell. 2019 Apr 18;74(2):378-392.e5. (PMID: 30904392); Nat Cell Biol. 2010 Nov;12(11):1035-45. (PMID: 20890297); Kidney Int. 1996 Jul;50(1):208-18. (PMID: 8807590); Cell Stem Cell. 2011 May 6;8(5):580-93. (PMID: 21549331); J Biol Chem. 2011 Apr 8;286(14):12461-74. (PMID: 21300793); J Cell Sci. 2014 Jun 1;127(Pt 11):2483-92. (PMID: 24706948); J Biol Chem. 2007 Nov 9;282(45):32549-60. (PMID: 17855357); J Biol Chem. 2008 Mar 7;283(10):6300-11. (PMID: 18162466); Dev Cell. 2014 Aug 25;30(4):449-62. (PMID: 25158854); Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1702-1716. (PMID: 29499326); Trends Mol Med. 2007 Jun;13(6):231-40. (PMID: 17524805); Curr Biol. 2010 Oct 26;20(20):1809-18. (PMID: 20933426); J Clin Invest. 2000 Jun;105(12):1711-21. (PMID: 10862786); Development. 2005 Mar;132(6):1247-60. (PMID: 15716348); EMBO J. 2018 Jul 2;37(13):. (PMID: 29858227); Trends Cell Biol. 2015 Aug;25(8):476-85. (PMID: 25941134); Am J Physiol Lung Cell Mol Physiol. 2010 Oct;299(4):L542-9. (PMID: 20693315); Cell. 1991 Sep 6;66(5):1027-36. (PMID: 1716180); J Clin Invest. 1972 Apr;51(4):796-804. (PMID: 4335444); Nat Cell Biol. 2006 Jun;8(6):594-600. (PMID: 16648843) |
| Contributed Indexing: | Keywords: 3D culture; AMPK; CFTR; Epithelial; Lumenogenesis; PHLPP |
| Substance Nomenclature: | 0 (CFTR protein, human); 0 (Nuclear Proteins); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.1.3.16 (PHLPP1 protein, human); EC 3.1.3.16 (Phosphoprotein Phosphatases); EC 3.1.3.2 (Phosphoric Monoester Hydrolases) |
| Entry Date(s): | Date Created: 20220823 Date Completed: 20220825 Latest Revision: 20250728 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9534488 |
| DOI: | 10.1242/dev.200955 |
| PMID: | 35997536 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't