دورية أكاديمية
Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms.
| العنوان: | Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms. |
|---|---|
| المؤلفون: | Drinane MC; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Yaqoob U; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Yu H; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Beijing Youan Hospital, Capital Medical University, Beijing, China., Luo F; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Medical College, Xiamen University, Xiamen, Fujian, China., Greuter T; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Arab JP; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Kostallari E; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Verma VK; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Maiers J; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., De Assuncao TM; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Simons M; Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut, USA., Mukhopadhyay D; Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA., Kisseleva T; Department of Surgery, UCSD, California, USA., Brenner DA; Department of Surgery, UCSD, California, USA., Urrutia R; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Lomberk G; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Gao Y; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Ligresti G; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Tschumperlin DJ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Revzin A; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Cao S; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Shah VH; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. |
| المصدر: | JCI insight [JCI Insight] 2017 Dec 21; Vol. 2 (24). Date of Electronic Publication: 2017 Dec 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Adaptor Proteins, Signal Transducing/*physiology , Liver Cirrhosis/*metabolism , Receptors, Platelet-Derived Growth Factor/*biosynthesis, Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Animals ; Autophagy/physiology ; Cell Movement/physiology ; Down-Regulation/physiology ; Gene Knockdown Techniques ; Hepatic Stellate Cells/metabolism ; Hepatic Stellate Cells/pathology ; Hepatic Stellate Cells/physiology ; Humans ; Liver Cirrhosis/genetics ; Liver Cirrhosis/pathology ; Liver Cirrhosis/prevention & control ; Mice, Knockout ; Pulmonary Fibrosis/metabolism ; Receptors, Platelet-Derived Growth Factor/genetics ; Receptors, Platelet-Derived Growth Factor/physiology ; Ubiquitin/metabolism ; Up-Regulation/physiology |
| مستخلص: | The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis. |
| References: | Nucleic Acids Res. 2013 Jan;41(Database issue):D344-7. (PMID: 23161676) J Microsc. 2006 Dec;224(Pt 3):213-32. (PMID: 17210054) J Cell Biol. 2015 Sep 14;210(6):973-89. (PMID: 26347139) Biores Open Access. 2015 Jan 01;4(1):97-108. (PMID: 26309786) Clin Liver Dis. 2014 May;18(2):281-91. (PMID: 24679494) Anal Chem. 2002 Oct 15;74(20):5383-92. (PMID: 12403597) J Biol Chem. 2014 May 30;289(22):15798-809. (PMID: 24759103) ACS Chem Biol. 2015 Mar 10;:null. (PMID: 25756300) J Biol Chem. 2006 Dec 22;281(51):39105-13. (PMID: 17071613) Gastroenterology. 2014 May;146(5):1339-50.e1. (PMID: 24503129) J Biol Chem. 2003 Apr 18;278(16):14013-9. (PMID: 12588875) EMBO Mol Med. 2015 Feb 13;7(3):332-8. (PMID: 25680861) Autophagy. 2013 Aug;9(8):1131-58. (PMID: 23774882) Lab Invest. 2015 Oct;95(10):1218. (PMID: 26412498) Toxicol Sci. 2012 Jun;127(2):438-50. (PMID: 22491424) Nucleic Acids Res. 2015 Jul 1;43(W1):W566-70. (PMID: 25969447) PLoS One. 2014 Mar 25;9(3):e92925. (PMID: 24667490) J Hepatol. 2011 Dec;55(6):1353-60. (PMID: 21803012) Gene Expr. 2015;16(3):109-27. (PMID: 25700367) Am J Physiol Gastrointest Liver Physiol. 2014 Oct 1;307(7):G749-59. (PMID: 25169976) Cancer Lett. 2013 Oct 1;339(1):70-81. (PMID: 23879969) Dig Dis Sci. 2012 Mar;57(3):660-6. (PMID: 21989821) J Biol Chem. 2007 Sep 14;282(37):27215-28. (PMID: 17623675) Mol Cancer Res. 2010 Dec;8(12 ):1591-600. (PMID: 21047775) J Hepatol. 2012 Nov;57(5):967-73. (PMID: 22820479) J Clin Invest. 2015 Jan;125(1):42-6. (PMID: 25654549) Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834) J Clin Invest. 2015 Jan;125(1):47-54. (PMID: 25654550) J Pathol. 2012 Jul;227(3):325-35. (PMID: 22262369) N Engl J Med. 2010 Nov 4;363(19):1863-4. (PMID: 21047232) Gastroenterology. 2012 Oct;143(4):890-2. (PMID: 22917861) Dev Cell. 2006 Jun;10(6):783-95. (PMID: 16740480) Cancer Res. 2012 Aug 15;72(16):4047-59. (PMID: 22738912) Autophagy. 2016;12 (1):1-222. (PMID: 26799652) Am J Pathol. 2017 Jan;187(1):134-145. (PMID: 27840081) Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9448-53. (PMID: 22566629) Exp Mol Med. 2013 Jun 07;45:e26. (PMID: 23743496) PLoS One. 2014 Dec 03;9(12 ):e114409. (PMID: 25469510) Am J Pathol. 2011 Jun;178(6):2708-15. (PMID: 21641393) Biomed Microdevices. 2011 Jun;13(3):539-48. (PMID: 21424383) J Cell Biol. 2010 Aug 23;190(4):693-706. (PMID: 20733059) Cytokine. 2005 Sep 7;31(5):349-57. (PMID: 16039137) Hepatology. 2014 Jul;60(1):334-48. (PMID: 24619965) PLoS One. 2013 Nov 15;8(11):e80143. (PMID: 24260349) J Cell Sci. 2013 Jun 15;126(Pt 12):2561-70. (PMID: 23781020) Blood. 2016 Feb 18;127(7):882-92. (PMID: 26286850) J Biol Chem. 2009 Nov 6;284(45):31484-92. (PMID: 19758991) Anal Chem. 2003 Sep 1;75(17):4646-58. (PMID: 14632076) J Cell Sci. 2014 Mar 1;127(Pt 5):994-1006. (PMID: 24413169) Gastroenterology. 2012 Apr;142(4):938-46. (PMID: 22240484) Circ Res. 2013 Oct 12;113(9):1076-86. (PMID: 23897694) Gut. 2015 May;64(5):830-41. (PMID: 25681399) J Clin Invest. 2010 Jul;120(7):2379-94. (PMID: 20577048) Nat Med. 2006 Apr;12(4):410-6. (PMID: 16532004) Autophagy. 2012 Jan;8(1):126-8. (PMID: 22082960) Cell Signal. 2015 Sep;27(9):1816-23. (PMID: 26071201) J Biol Chem. 2010 Oct 8;285(41):31840-8. (PMID: 20675371) |
| معلومات مُعتمدة: | R01 DK059615 United States DK NIDDK NIH HHS; R01 AA021171 United States AA NIAAA NIH HHS; P42 ES010337 United States ES NIEHS NIH HHS; P30 DK084567 United States DK NIDDK NIH HHS; R37 AA021171 United States AA NIAAA NIH HHS; R01 DK052913 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: Hepatology; Signal transduction |
| المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Gipc1 protein, mouse) 0 (Ubiquitin) EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor) |
| تواريخ الأحداث: | Date Created: 20171222 Date Completed: 20190708 Latest Revision: 20191210 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5752303 |
| DOI: | 10.1172/jci.insight.92821 |
| PMID: | 29263300 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2379-3708 |
|---|---|
| DOI: | 10.1172/jci.insight.92821 |