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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 呂勝春(Sheng-Chung Lee) | |
dc.contributor.author | Hsin-Yun Chang | en |
dc.contributor.author | 張馨勻 | zh_TW |
dc.date.accessioned | 2021-05-16T16:18:15Z | - |
dc.date.available | 2015-09-24 | |
dc.date.available | 2021-05-16T16:18:15Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-15 | |
dc.identifier.citation | 1. Wang Z, Takemori H, Halder SK, Nonaka Y, Okamoto M: Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal. FEBS Lett 1999, 453:135-139.
2. Katoh Y, Takemori H, Horike N, Doi J, Muraoka M, Min L, Okamoto M: Salt-inducible kinase (SIK) isoforms: their involvement in steroidogenesis and adipogenesis. Mol Cell Endocrinol 2004, 217:109-112. 3. Okamoto M, Takemori H, Katoh Y: Salt-inducible kinase in steroidogenesis and adipogenesis. Trends Endocrinol Metab 2004, 15:21-26. 4. Horike N, Takemori H, Katoh Y, Doi J, Min L, Asano T, Sun XJ, Yamamoto H, Kasayama S, Muraoka M, et al.: Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem 2003, 278:18440-18447. 5. Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR, 3rd, Takemori H, et al.: The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 2004, 119:61-74. 6. Muraoka M, Fukushima A, Viengchareun S, Lombes M, Kishi F, Miyauchi A, Kanematsu M, Doi J, Kajimura J, Nakai R, et al.: Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1alpha and UCP-1 gene expression in brown adipocytes. Am J Physiol Endocrinol Metab 2009, 296:E1430-1439. 7. Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R: Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest 2010, 120:4316-4331. 8. Horike N, Kumagai A, Shimono Y, Onishi T, Itoh Y, Sasaki T, Kitagawa K, Hatano O, Takagi H, Susumu T, et al.: Downregulation of SIK2 expression promotes the melanogenic program in mice. Pigment Cell Melanoma Res 2010, 23:809-819. 9. Sasaki T, Takemori H, Yagita Y, Terasaki Y, Uebi T, Horike N, Takagi H, Susumu T, Teraoka H, Kusano K, et al.: SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron 2011, 69:106-119. 10. Ahmed AA, Lu Z, Jennings NB, Etemadmoghadam D, Capalbo L, Jacamo RO, Barbosa-Morais N, Le XF, Vivas-Mejia P, Lopez-Berestein G, et al.: SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell 2010, 18:109-121. 11. Liu Y, Poon V, Sanchez-Watts G, Watts AG, Takemori H, Aguilera G: Salt-inducible kinase is involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats. Endocrinology 2012, 153:223-233. 12. Yang FC, Tan BC, Chen WH, Lin YH, Huang JY, Chang HY, Sun HY, Hsu PH, Liou GG, Shen J, et al.: Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy. J Biol Chem 2013, 288:6227-6237. 13. Schonthal AH: Role of PP2A in intracellular signal transduction pathways. Front Biosci 1998, 3:D1262-1273. 14. Janssens V, Goris J: Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001, 353:417-439. 15. Sontag E: Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell Signal 2001, 13:7-16. 16. Li X, Virshup DM: Two conserved domains in regulatory B subunits mediate binding to the A subunit of protein phosphatase 2A. Eur J Biochem 2002, 269:546-552. 17. Bontron S, Jaquenoud M, Vaga S, Talarek N, Bodenmiller B, Aebersold R, De Virgilio C: Yeast endosulfines control entry into quiescence and chronological life span by inhibiting protein phosphatase 2A. Cell Rep 2013, 3:16-22. 18. Chen J, Martin BL, Brautigan DL: Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 1992, 257:1261-1264. 19. Cho US, Xu W: Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 2007, 445:53-57. 20. Longin S, Zwaenepoel K, Louis JV, Dilworth S, Goris J, Janssens V: Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit. J Biol Chem 2007, 282:26971-26980. 21. Li Y, Wei H, Hsieh TC, Pallas DC: Cdc55p-mediated E4orf4 growth inhibition in Saccharomyces cerevisiae is mediated only in part via the catalytic subunit of protein phosphatase 2A. J Virol 2008, 82:3612-3623. 22. Zhao HH, Di J, Liu WS, Liu HL, Lai H, Lu YL: Involvement of GSK3 and PP2A in ginsenoside Rb1's attenuation of aluminum-induced tau hyperphosphorylation. Behav Brain Res 2013, 241:228-234. 23. Yu H: PP2A as a mercenary for warring kinases in the egg. Proc Natl Acad Sci U S A 2007, 104:17245-17246. 24. De Baere I, Derua R, Janssens V, Van Hoof C, Waelkens E, Merlevede W, Goris J: Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue. Biochemistry 1999, 38:16539-16547. 25. Leulliot N, Quevillon-Cheruel S, Sorel I, Li de La Sierra-Gallay I, Collinet B, Graille M, Blondeau K, Bettache N, Poupon A, Janin J, et al.: Structure of protein phosphatase methyltransferase 1 (PPM1), a leucine carboxyl methyltransferase involved in the regulation of protein phosphatase 2A activity. J Biol Chem 2004, 279:8351-8358. 26. Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, Pallas DC: A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem 1999, 274:14382-14391. 27. Al-Hakim AK, Goransson O, Deak M, Toth R, Campbell DG, Morrice NA, Prescott AR, Alessi DR: 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK. J Cell Sci 2005, 118:5661-5673. 28. Sjostrom M, Stenstrom K, Eneling K, Zwiller J, Katz AI, Takemori H, Bertorello AM: SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process. Proc Natl Acad Sci U S A 2007, 104:16922-16927. 29. Lee CW: Functional interaction between SIK2 and PP2A. In 分子醫學研究所. Edited by: 臺灣大學; 2012:1-52. 30. Heroes E, Lesage B, Gornemann J, Beullens M, Van Meervelt L, Bollen M: The PP1 binding code: a molecular-lego strategy that governs specificity. FEBS J 2013, 280:584-595. 31. Chatterjee J, Kohn M: Targeting the untargetable: recent advances in the selective chemical modulation of protein phosphatase-1 activity. Curr Opin Chem Biol 2013, 17:361-368. 32. Choy MS, Page R, Peti W: Regulation of protein phosphatase 1 by intrinsically disordered proteins. Biochem Soc Trans 2012, 40:969-974. 33. Bielas SL, Serneo FF, Chechlacz M, Deerinck TJ, Perkins GA, Allen PB, Ellisman MH, Gleeson JG: Spinophilin facilitates dephosphorylation of doublecortin by PP1 to mediate microtubule bundling at the axonal wrist. Cell 2007, 129:579-591. 34. Pinheiro AS, Marsh JA, Forman-Kay JD, Peti W: Structural signature of the MYPT1-PP1 interaction. J Am Chem Soc 2011, 133:73-80. 35. Toth A, Kiss E, Gergely P, Walsh MP, Hartshorne DJ, Erdodi F: Phosphorylation of MYPT1 by protein kinase C attenuates interaction with PP1 catalytic subunit and the 20 kDa light chain of myosin. FEBS Lett 2000, 484:113-117. 36. Liu L, Xie N, Rennie P, Challis JR, Gleave M, Lye SJ, Dong X: Consensus PP1 binding motifs regulate transcriptional corepression and alternative RNA splicing activities of the steroid receptor coregulators, p54nrb and PSF. Mol Endocrinol 2011, 25:1197-1210. 37. Brady MJ, Nairn AC, Saltiel AR: The regulation of glycogen synthase by protein phosphatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in insulin action. J Biol Chem 1997, 272:29698-29703. 38. Chin AC, Vergnolle N, MacNaughton WK, Wallace JL, Hollenberg MD, Buret AG: Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. Proc Natl Acad Sci U S A 2003, 100:11104-11109. 39. Garcia A, Cayla X, Guergnon J, Dessauge F, Hospital V, Rebollo MP, Fleischer A, Rebollo A: Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie 2003, 85:721-726. 40. Posch M, Khoudoli GA, Swift S, King EM, Deluca JG, Swedlow JR: Sds22 regulates aurora B activity and microtubule-kinetochore interactions at mitosis. J Cell Biol 2010, 191:61-74. 41. Tournebize R, Andersen SS, Verde F, Doree M, Karsenti E, Hyman AA: Distinct roles of PP1 and PP2A-like phosphatases in control of microtubule dynamics during mitosis. EMBO J 1997, 16:5537-5549. 42. Wu JQ, Guo JY, Tang W, Yang CS, Freel CD, Chen C, Nairn AC, Kornbluth S: PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation. Nat Cell Biol 2009, 11:644-651. 43. Naqib F, Sossin WS, Farah CA: Molecular determinants of the spacing effect. Neural Plast 2012, 2012:581291. 44. Chen WH: Functional interaction between Salt-inducible kinase 2 and p97/VCP regulates ER-associated degradation and application of nanodiamond in proteomic research. In 分子醫學研究所. Edited by: 臺灣大學; 2007:1-118. 45. Ballar P, Pabuccuoglu A, Kose FA: Different p97/VCP complexes function in retrotranslocation step of mammalian ER-associated degradation (ERAD). Int J Biochem Cell Biol 2011, 43:613-621. 46. Bug M, Meyer H: Expanding into new markets--VCP/p97 in endocytosis and autophagy. J Struct Biol 2012, 179:78-82. 47. Dargemont C, Ossareh-Nazari B: Cdc48/p97, a key actor in the interplay between autophagy and ubiquitin/proteasome catabolic pathways. Biochim Biophys Acta 2012, 1823:138-144. 48. Kano F, Kondo H, Yamamoto A, Kaneko Y, Uchiyama K, Hosokawa N, Nagata K, Murata M: NSF/SNAPs and p97/p47/VCIP135 are sequentially required for cell cycle-dependent reformation of the ER network. Genes Cells 2005, 10:989-999. 49. Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hubscher U, Meyer H, Ramadan K: The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat Cell Biol 2011, 13:1376-1382. 50. Uchiyama K, Kondo H: p97/p47-Mediated biogenesis of Golgi and ER. J Biochem 2005, 137:115-119. 51. Lavoie C, Chevet E, Roy L, Tonks NK, Fazel A, Posner BI, Paiement J, Bergeron JJ: Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro. Proc Natl Acad Sci U S A 2000, 97:13637-13642. 52. Li G, Zhao G, Schindelin H, Lennarz WJ: Tyrosine phosphorylation of ATPase p97 regulates its activity during ERAD. Biochem Biophys Res Commun 2008, 375:247-251. 53. Tiganis T, Flint AJ, Adam SA, Tonks NK: Association of the T-cell protein tyrosine phosphatase with nuclear import factor p97. J Biol Chem 1997, 272:21548-21557. 54. Klein JB, Barati MT, Wu R, Gozal D, Sachleben LR, Jr., Kausar H, Trent JO, Gozal E, Rane MJ: Akt-mediated valosin-containing protein 97 phosphorylation regulates its association with ubiquitinated proteins. J Biol Chem 2005, 280:31870-31881. 55. Livingstone M, Ruan H, Weiner J, Clauser KR, Strack P, Jin S, Williams A, Greulich H, Gardner J, Venere M, et al.: Valosin-containing protein phosphorylation at Ser784 in response to DNA damage. Cancer Res 2005, 65:7533-7540. 56. Vandermoere F, El Yazidi-Belkoura I, Slomianny C, Demont Y, Bidaux G, Adriaenssens E, Lemoine J, Hondermarck H: The valosin-containing protein (VCP) is a target of Akt signaling required for cell survival. J Biol Chem 2006, 281:14307-14313. 57. Jiang N, Shen Y, Fei X, Sheng K, Sun P, Qiu Y, Larner J, Cao L, Kong X, Mi J: Valosin-containing protein regulates the proteasome-mediated degradation of DNA-PKcs in glioma cells. Cell Death Dis 2013, 4:e647. 58. Cloutier P, Lavallee-Adam M, Faubert D, Blanchette M, Coulombe B: A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity. PLoS Genet 2013, 9:e1003210. 59. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN: Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 2002, 110:479-488. 60. Lu J, McKinsey TA, Nicol RL, Olson EN: Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci U S A 2000, 97:4070-4075. 61. Walkinshaw DR, Weist R, Kim GW, You L, Xiao L, Nie J, Li CS, Zhao S, Xu M, Yang XJ: The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases. J Biol Chem 2013, 288:9345-9362. 62. Virshup DM: Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol 2000, 12:180-185. 63. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM: Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 2007, 171:513-524. 64. Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Eynde A, Nicolaescu E, Lesage B, Bollen M: Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol 2009, 16:365-371. 65. Ruiz A, Xu X, Carlson M: Roles of two protein phosphatases, Reg1-Glc7 and Sit4, and glycogen synthesis in regulation of SNF1 protein kinase. Proc Natl Acad Sci U S A 2011, 108:6349-6354. 66. Huang HB, Horiuchi A, Goldberg J, Greengard P, Nairn AC: Site-directed mutagenesis of amino acid residues of protein phosphatase 1 involved in catalysis and inhibitor binding. Proc Natl Acad Sci U S A 1997, 94:3530-3535. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/5907 | - |
dc.description.abstract | 蛋白激酶SIK2屬於AMPK家族中的一員。目前已知SIK2在胰島素和葡萄醣代謝扮演重要角色,但其餘相關作用都還未知。實驗室目前已知SIK2的激酶活性會受到p300/CBP的乙醯化和HDAC的去乙醯化所調控。為研究SIK2之功能,從其交互作用的蛋白質著手是一常用的研究法;SIK2是AMPK家族中唯一會和p97/VCP和蛋白磷酸水解酶PP2A有交互作用的成員。另外,SIK2和p97/VCP的交互作用會促進內質網蛋白質降解。本研究主要針對SIK2和PP2A的功能及交互作用探討,同時也會討論SIK2和PP1的交互作用。我的主要目標是研究調控SIK2-PP2A複合體的形成的相關機制。SIK2只會和完整三個次單元組成之具活性之PP2A結合且PP2A依然保有磷酸水解酶的活性。由於SIK2上的羧丁胺酸Thr175受到磷酸化也顯示在SIK2-PP2A複合體中的SIK2可能保有活性。此外,我觀察到當利用高濃度的okadaic acid (OA)處理的HEK293T細胞,在蛋白質電泳當中,SIK2會出現泳動遲至的現象。而磷酸化的SIK2/T175在高濃度OA (大於0.3 μΜ)處理下可以被偵測到。這個結果說明PP1可能會影響SIK2相關的磷酸化機制。實驗結果發現SIK2和其結合的p97/VCP都會與PP1有交互作用。PP1與SIK2蛋白質的結合點位在RVGF (胺基酸位置16-19), 但與p97/VCP產生交互作用結合點尙待鑑定。最後,我也證明SIK2可能參與在MEF2C所調控的基因表現。 | zh_TW |
dc.description.abstract | Salt-inducible kinase 2 (SIK2) is a member of AMPK family. Except for its roles in insulin signaling and glucose metabolism, the functions of SIK2 remain largely unknown. Our laboratory has demonstrated that the SIK2 kinase activity may be regulated by p300/CBP-mediated acetylation and HDAC6-induced deacetylation. SIK2 is the only member of the AMPK family capable of interacting with p97/VCP and protein phosphatase 2A (PP2A). Furthermore, interaction between SIK2 and p97/VCP was shown to facilitate ER-associated protein degradation (ERAD). In this thesis, I present results of physical and functional interactions between SIK2 and PP2A as well as protein phosphatase 1 (PP1). My major aim is to study the physiological cues responsible for regulation of SIK2 and PP2A complex formation. One of the major findings was that SIK2 interacts with PP2A holoenzyme. The elevated phosphorylation of SIK2 at Thr175 in SIK2-PP2A complex suggested that SIK2 activity was preserved in the complex. The kinase activity of SIK2-PP2A complex was further demonstrated by phosphorylation of a GST-syntide-2 substrate. In addition to PP2A, I have observed that when HEK293T cells were treated with high, but not low, concentration of okadaic acid (OA, ~0.3 μΜ vs. 0.1 μΜ), the mobility of SIK2 in SDS gel was retarded. The phosphorylated SIK2/T175 level of OA-treated sample is higher than that of control. These results suggest that PP1 inactivation may contribute to the mobility shift and hyper-phosphorylation of SIK2. Further experiments have uncovered that SIK2 and its associated p97/VCP protein both interact with PP1. The docking site of PP1 essential for its binding to SIK2 has been identified in the RVGF (amino acid 16-19) region while the docking site(s) in p97/VCP remains to be determined. Finally, I have demonstrated that SIK2 plays regulatory functions in MEF2C-mediated gene expression. | en |
dc.description.provenance | Made available in DSpace on 2021-05-16T16:18:15Z (GMT). No. of bitstreams: 1 ntu-102-R00448003-1.pdf: 1017845 bytes, checksum: 5618b5e4e5ce375163cd23fff3a6562b (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii Abstract iv Contents vi Introduction 1 Materials and methods 6 Antibodies, drugs and plasmids 6 Site-directed mutation in plasmid 6 Cell culture and transfection 7 Lentivirus-shSIK2-mediated knockdown of SIK2 7 Protein extraction 8 Immunoblot analysis 8 Immunoprecipitation 8 In vitro kinase assay 9 Reporter assay 9 Statistical analysis 10 Results 11 SIK2 interacts with PP2A holoenzyme 11 SIK2 activity is preserved in SIK2-PP2A complex 11 Interaction between SIK2 and PP1 12 SIK2 regulates MEF2C-mediated gene expression 14 Discussion 16 References 20 Figures 27 Figure 1. PP2A holoenzyme is required for its interaction with SIK2 27 Figure 2. SIK2 kinase activity is preserved in SIK2-PP2A complex 29 Figure3. High concentration of OA treatments resulted in elevated phosphorylation level of SIK2-T175 31 Figure 4. SIK2 and p97/VCP interact with PP1 32 Figure 5. SIK2 regulates MEF2C-mediated transcription 34 | |
dc.language.iso | en | |
dc.title | 蛋白激酶SIK2和蛋白磷酸水解酶PP2A和PP1的交互調控 | zh_TW |
dc.title | Functional interaction between SIK2 and PP2A or PP1 phosphatase | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 譚賢明(Bertrand Ching-Ming Tan),吳君泰(June-Tai Wu) | |
dc.subject.keyword | SIK2,PP2A,PP1,p97/VCP,RVxF motif,MEF2C調控轉錄機制, | zh_TW |
dc.subject.keyword | SIK2,PP2A,PP1,p97/VCP,RVxF motif,MEF2C-mediated transcription, | en |
dc.relation.page | 35 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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