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  1. NTU Theses and Dissertations Repository
  2. 醫學院
  3. 免疫學研究所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45668
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dc.contributor.advisor繆希椿
dc.contributor.authorYi-Wei Sunen
dc.contributor.author孫宜緯zh_TW
dc.date.accessioned2021-06-15T04:44:26Z-
dc.date.available2020-08-05
dc.date.copyright2010-09-09
dc.date.issued2010
dc.date.submitted2010-08-09
dc.identifier.citation1. Mustelin, T., Vang, T. &Bottini, N. Protein tyrosine phosphatases and the immune response. Nature reviews. Immunology5, 43-57(2005).

2. Alonso, A. et al. protein Tyrosine Phosphatases in the Human Genome. Cell117, 699-711(2004).

3. Andersen, J.N. et al. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology18, 8-30(2004).
4. Gold, M.R. et al. Tyrosine phosphorylation of components of the B-cell antigen receptors following receptor crosslinking. Proceedings of the National Academy of Sciences of the United States of America88, 3436-40(1991).
5. Mustelin, T. &Taskén, K. Positive and negative regulation of T-cell activation through kinases and phosphatases. The Biochemical journal371, 15-27(2003).
6. Vang, T. et al. Protein tyrosine phosphatases in autoimmunity. Annual review of immunology26, 29-55(2008).
7. Cohen, S. et al. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood93, 2013-24(1999).
8. Gregorieff A, Cloutier JF, Veillette A. Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinasep50(csk). J BiolChem273,13217–13222(1998).
9. Côté, J. et al. PSTPIP is a substrate of PTP-PEST and serves as a scaffold guiding PTP-PEST toward a specific dephosphorylation of WASP. The Journal of biological chemistry277, 2973-86(2002).
10. Matthews, R.J. et al. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Molecular and cellular biology12, 2396-405(1992).
11. Jordan MS, Singer AL, Koretzky GA. Adaptors as central mediators of signal transduction in immune cells.Nat Immunol4, 110–116(2003).
12. Cloutier JF, Veillette A. Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J15, 4909-4918(1996).
13. Gj¨ orloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur. J. Immunol29, 3845–3854 (1999).
14. Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J. Biol. Chem. 281, 11002–11010 (2006).
15. Cloutier JF, Veillette A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med.189, 111–121 (1999).
16. Begovich, A.B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet75, 330-337 (2004).
17. Kenneth M. Kaufman, Jennifer A. Kelly, Billy J. Herring, Adam J. Adler,
Stuart B. Glenn, BahramNamjou, Summer G. Frank, Sarah L. Dawson, Gail R. Bruner,Judith A. James, and John B. Harley. Evaluation of the Genetic Association of thePTPN22 R620W Polymorphism in Familial and Sporadic Systemic Lupus Erythematosus.Arthritis Rheum54, 2533–2540 (2006).
18. Torkel Vang, Mauro Congia, Maria DolorettaMacis et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet37, 1317-1319 (2005).
19. Kiminori Hasegawa, Flavius Martin, Guangming Huang, Dan Tumas, Lauri Diehl, Andrew C. Chan. PEST Domain–Enriched Tyrosine Phosphatase (PEP) Regulation of Effector/Memory T Cells.Science303, 685-689 (2004).
20. D, G. & U., K. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol.15, 607-670 (1999).
21. Robbins, J. et al. Two Interdependent Basic Domains in Nucleoplasmin Nuclear Targeting Sequence : Identification of a Class of Bipartite Nuclear Targeting Sequence. Cell64, 615-623 (1991).
22. Daniel Kalderon, William D. Richardson, Alexander F. Markham & Alan E. Smith. Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature311, 33-38 (1984).
23. Won-Ki Huh, James V. Falvo, Luke C. Gerke, Adam S. Carroll, Russell W. Howson, Jonathan S. Weissman& Erin K. O’Shea. Global analysis of protein localization in budding yeast.Nature425, 686-691 (2003).
24. Hoeve, J. et al. Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase. Society22, 5662-5668 (2002).
25. Aoki, N. A Nuclear Protein Tyrosine Phosphatase TC-PTP Is a Potential Negative Regulator of the PRL-Mediated Signaling Pathway: Dephosphorylation and Deactivation of Signal Transducer and Activator of Transcription 5a and 5b by TC-PTP in Nucleus. Molecular Endocrinology16, 58-69 (2002).
26. Yamamoto, T. et al. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochemical and Biophysical Research Communications297, 811-817 (2002).
27. Doody, K.M.,Bourdeau, A. & Tremblay, M.L. T-cell protein tyrosine phosphatase is a key regulator in immune cell signaling: lessons from the knockout mouse model and implications in human disease. Immunological reviews228, 325-41 (2009).
28. Andre´ Veillette, Inmoo Rhee, Cleiton Martins Souza, Dominique Davidson. PEST family phosphatases in immunity autoimmunity, and autoinflammatorydisorders.Immunological Reviews228, 312–324 (2009).
29. Healy, a.M. et al. Identification of a bipartite nuclear localization sequence necessary for nuclear import of 5-lipoxygenase. The Journal of biological chemistry274, 29812-8(1999).
30. Cassola, A. &Frasch, A.C. An RNA recognition motif mediates the nucleocytoplasmic transport of a trypanosome RNA-binding protein. The Journal of biological chemistry284, 35015-28(2009).
31. Lange, a. et al. Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin .Journal of Biological Chemistry282, 5101-5105(2006).
dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45668-
dc.description.abstract蛋白酪胺酸磷酸酶非受體二十二型為在細胞質中負向調控T細胞訊息路徑的酪胺酸磷酸酶。我們實驗室近來在細胞核中發現此酵素。然而,蛋白酪胺酸磷酸酶非受體二十二型進入細胞核的機制仍未明。先前已知帶有細胞核定位訊號的蛋白質可以被運送進細胞核中。我們證實蛋白酪胺酸磷酸脢非受體二十二型的區域C為潛在的細胞核定位訊號,而且區域C對於細胞核運送是必須存在的。帶有區域C被刪除的蛋白酪胺酸磷酸脢非受體二十二型之螢光表現質體在轉染細胞後,發現其螢光無法分布於細胞核中。從點突變實驗中,我們也證實蛋白酪胺酸磷酸脢非受體二十二型的A和B點突變之後,將會損壞此蛋白質進入細胞核的能力。進一步研究負責運送蛋白酪胺酸磷酸脢非受體二十二型進入細胞質的胺基酸序列之實驗中,我們將區域I或/和區域II和雙倍的綠色螢光蛋白克隆在一起,製造出融合蛋白,驗證這些區域對於將綠色螢光蛋白送運進入細胞核的能力為何。從實驗結果發現,蛋白酪胺酸磷酸酶非受體二十二型的區域I能將綠色螢光蛋白運送進入細胞核。我們的實驗指出蛋白酪胺酸磷酸酶非受體二十二型的區域I為細胞核定位訊號且在運送蛋白質進入細胞核中扮演十分重要的角色。zh_TW
dc.description.abstractPTPN22 is a protein tyrosine phosphatase that participates in the negative regulation of T cell signaling in cytoplasm. Recently, our lab shows that PTPN22 could locate inside the nucleus. However, the molecular mechanism of PTPN22 in nuclear import is poorly understood. Proteins that import from the cytosol to the nucleus contain basic amino acids-rich nucleus localization signal (NLS). We demonstrated Region C of PTPN22 was a potential NLS and necessary for nuclear import. Cells transfected with fluorescent vectors encoding Region C-deleted PTPN22 showed clear nuclear distribution. Mutation analysis showed A and B mutations of PTPN22 are critical sites for nuclear import of PTPN22, because the Mutant A and B impaired the capability of nuclear transport of PTPN22. To further identify sequences responsible for nuclear import of PTPN22, Region I or/and Region II was fused with double GFP and examined their abilities to target GFP into the nucleus. The results showed that Region I of PTPN22 could import GFP into the nucleus. Our data indicated that the Region I of PTPN22 served as NLS and played a vital role in nuclear import.en
dc.description.provenanceMade available in DSpace on 2021-06-15T04:44:26Z (GMT). No. of bitstreams: 1
ntu-99-R97449010-1.pdf: 7200766 bytes, checksum: e034c796f54c868eab4201f3ab37b766 (MD5)
Previous issue date: 2010
en
dc.description.tableofcontentsAcknowledgement i
Abstract ii
中文摘要 iii
Table of contents iv
List of figures vi
Chapter I Introduction 1
1.1 Tyrosine phosphorylation 1
1.2 Protein tyrosine phosphatase 2
1.3 PTPN22 3
1.4 Biological function of PTPN22 4
1.5 Negative regulation of T-cell activation by PTPN22 5
1.6 The role of PTPN22 in autoimmune disease 5
2.1 Transport between cytoplasm and nucleus 7
2.2 Nuclear localization signals (NLS) 8
2.3 The nuclear import pathway 9
3.1 Rationale to study NLS of PTPN22 10
Chapter II Material and Methods 11
2.1 Experimental procedures 11
2.2 Experimental materials 25
Chapter III Result 37
3.1 Identification of PTPN22 Region C as potential nucleus localization signal (NLS) 37
3.2 Examine the role of Region D of PTPN22 in nuclear transport 38
3.3 PTPN22 Mutant A has an impaired capability of nuclear transport of PTPN22 39
3.4 The impairment of nuclear transport of PTPN22 Mutant B 40
3.5 Region I, but not Region II, of PTPN22 could import the irrelevant protein into the nucleus 41
Chapter IV Discussion 43
Chapter V Figure 49
Chapter VI References 73
dc.language.isoen
dc.subject非受體二十二型zh_TW
dc.subject蛋白酪胺酸磷酸&#37238zh_TW
dc.subjectPTPN22en
dc.subjectNLSen
dc.title鑑定蛋白酪胺酸磷酸酶(非受體二十二型)之細胞核定位訊號zh_TW
dc.titleIdentification of Nuclear Localization Signal (NLS) in PTPN22en
dc.typeThesis
dc.date.schoolyear98-2
dc.description.degree碩士
dc.contributor.oralexamcommittee賴明宗,司徒惠康
dc.subject.keyword蛋白酪胺酸磷酸&#37238,非受體二十二型,zh_TW
dc.subject.keywordPTPN22,NLS,en
dc.relation.page75
dc.rights.note有償授權
dc.date.accepted2010-08-09
dc.contributor.author-college醫學院zh_TW
dc.contributor.author-dept免疫學研究所zh_TW
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