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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳玉如(Yu-Ju Chen) | |
| dc.contributor.author | Chia-Feng Tsai | en |
| dc.contributor.author | 蔡家烽 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:33:00Z | - |
| dc.date.available | 2017-09-03 | |
| dc.date.copyright | 2014-09-03 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-05 | |
| dc.identifier.citation | 1. Hunter, T. (2000) Signaling--2000 and beyond. Cell 100, 113-127
2. Rane, S. G., and Reddy, E. P. (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19, 5662-5679 3. Giamas, G., Stebbing, J., Vorgias, C. E., and Knippschild, U. (2007) Protein kinases as targets for cancer treatment. Pharmacogenomics 8, 1005-1016 4. Daub, H. (2010) Kinase inhibitors: narrowing down the real targets. Nat. Chem. Biol. 6, 249-250 5. Malumbres, M., and Barbacid, M. (2007) Cell cycle kinases in cancer. Curr. Opin. Genet. Dev. 17, 60-65 6. Traxler, P., Bold, G., Buchdunger, E., Caravatti, G., Furet, P., Manley, P., O'Reilly, T., Wood, J., and Zimmermann, J. (2001) Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Revs 21, 499-512 7. Yu, L. R., Issaq, H. J., and Veenstra, T. D. (2007) Phosphoproteomics for the discovery of kinases as cancer biomarkers and drug targets. Proteomics Clin Appl 1, 1042-1057 8. Cohen, M. H., Williams, G. A., Sridhara, R., Chen, G., and Pazdur, R. (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8, 303-306 9. Johnson, J. R., Cohen, M., Sridhara, R., Chen, Y. F., Williams, G. M., Duan, J., Gobburu, J., Booth, B., Benson, K., Leighton, J., Hsieh, L. S., Chidambaram, N., Zimmerman, P., and Pazdur, R. (2005) Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin. Cancer Res. 11, 6414-6421 10. Sawyers, C. L. (2010) Even better kinase inhibitors for chronic myeloid leukemia. N. Engl. J. Med. 362, 2314-2315 11. Saglio, G., Kim, D. W., Issaragrisil, S., le Coutre, P., Etienne, G., Lobo, C., Pasquini, R., Clark, R. E., Hochhaus, A., Hughes, T. P., Gallagher, N., Hoenekopp, A., Dong, M., Haque, A., Larson, R. A., Kantarjian, H. M., and Investigators, E. N. (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 362, 2251-2259 12. Vogelstein, B., and Kinzler, K. W. (2004) Cancer genes and the pathways they control. Nat. Med. 10, 789-799 13. Boersema, P. J., Foong, L. Y., Ding, V. M., Lemeer, S., van Breukelen, B., Philp, R., Boekhorst, J., Snel, B., den Hertog, J., Choo, A. B., and Heck, A. J. (2010) In-depth qualitative and quantitative profiling of tyrosine phosphorylation using a combination of phosphopeptide immunoaffinity purification and stable isotope dimethyl labeling. Mol. Cell Proteomics 9, 84-99 14. Rush, J., Moritz, A., Lee, K. A., Guo, A., Goss, V. L., Spek, E. J., Zhang, H., Zha, X. M., Polakiewicz, R. D., and Comb, M. J. (2005) Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat. Biotechnol. 23, 94-101 15. Andersson, L., and Porath, J. (1986) Isolation of phosphoproteins by immobilized metal (Fe3+) affinity chromatography. Anal. Biochem. 154, 250-254 16. Posewitz, M. C., and Tempst, P. (1999) Immobilized gallium(III) affinity chromatography of phosphopeptides. Anal. Chem. 71, 2883-2892 17. Kokubu, M., Ishihama, Y., Sato, T., Nagasu, T., and Oda, Y. (2005) Specificity of immobilized metal affinity-based IMAC/C18 tip enrichment of phosphopeptides for protein phosphorylation analysis. Anal. Chem. 77, 5144-5154 18. Ndassa, Y. M., Orsi, C., Marto, J. A., Chen, S., and Ross, M. M. (2006) Improved immobilized metal affinity chromatography for large-scale phosphoproteomics applications. J. Proteome Res. 5, 2789-2799 19. Tsai, C. F., Wang, Y. T., Chen, Y. R., Lai, C. Y., Lin, P. Y., Pan, K. T., Chen, J. Y., Khoo, K. H., and Chen, Y. J. (2008) Immobilized metal affinity chromatography revisited: pH/acid control toward high selectivity in phosphoproteomics. J. Proteome Res. 7, 4058-4069 20. Ye, J., Zhang, X., Young, C., Zhao, X., Hao, Q., Cheng, L., and Jensen, O. N. (2010) Optimized IMAC-IMAC protocol for phosphopeptide recovery from complex biological samples. J. Proteome Res. 9, 3561-3573 21. Sano, A., and Nakamura, H. (2007) Evaluation of titanium and titanium oxides as chemo-affinity sorbents for the selective enrichment of organic phosphates. Anal Sci 23, 1285-1289 22. Bodenmiller, B., Mueller, L. N., Mueller, M., Domon, B., and Aebersold, R. (2007) Reproducible isolation of distinct, overlapping segments of the phosphoproteome. Nat. Methods 4, 231-237 23. Larsen, M. R., Thingholm, T. E., Jensen, O. N., Roepstorff, P., and Jorgensen, T. J. (2005) Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Mol. Cell Proteomics 4, 873-886 24. Sugiyama, N., Masuda, T., Shinoda, K., Nakamura, A., Tomita, M., and Ishihama, Y. (2007) Phosphopeptide enrichment by aliphatic hydroxy acid-modified metal oxide chromatography for nano-LC-MS/MS in proteomics applications. Mol. Cell Proteomics 6, 1103-1109 25. Jensen, S. S., and Larsen, M. R. (2007) Evaluation of the impact of some experimental procedures on different phosphopeptide enrichment techniques. Rapid Commun. Mass Spectrom. 21, 3635-3645 26. Zhou, H., Low, T. Y., Hennrich, M. L., van der Toorn, H., Schwend, T., Zou, H., Mohammed, S., and Heck, A. J. (2011) Enhancing the identification of phosphopeptides from putative basophilic kinase substrates using Ti (IV) based IMAC enrichment. Mol. Cell Proteomics 10, M110 006452 27. Thingholm, T. E., Jensen, O. N., Robinson, P. J., and Larsen, M. R. (2008) SIMAC (sequential elution from IMAC), a phosphoproteomics strategy for the rapid separation of monophosphorylated from multiply phosphorylated peptides. Mol. Cell Proteomics 7, 661-671 28. Villen, J., Beausoleil, S. A., Gerber, S. A., and Gygi, S. P. (2007) Large-scale phosphorylation analysis of mouse liver. Proc Natl Acad Sci U S A 104, 1488-1493 29. Choi, S., Kim, J., Cho, K., Park, G., Yoon, J. H., Park, S., Yoo, J. S., Ryu, S. H., Kim, Y. H., and Kim, J. (2010) Sequential Fe3O4/TiO2 enrichment for phosphopeptide analysis by liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. 24, 1467-1474 30. Hennrich, M. L., van den Toorn, H. W., Groenewold, V., Heck, A. J., and Mohammed, S. (2012) Ultra acidic strong cation exchange enabling the efficient enrichment of basic phosphopeptides. Anal. Chem. 84, 1804-1808 31. Dong, M., Ye, M., Cheng, K., Song, C., Pan, Y., Wang, C., Bian, Y., and Zou, H. (2012) Depletion of acidic phosphopeptides by SAX to improve the coverage for the detection of basophilic kinase substrates. J. Proteome Res. 11, 4673-4681 32. Chen, Y., Choong, L. Y., Lin, Q., Philp, R., Wong, C. H., Ang, B. K., Tan, Y. L., Loh, M. C., Hew, C. L., Shah, N., Druker, B. J., Chong, P. K., and Lim, Y. P. (2007) Differential expression of novel tyrosine kinase substrates during breast cancer development. Mol. Cell Proteomics 6, 2072-2087 33. Olsen, J. V., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P., and Mann, M. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635-648 34. Kruger, M., Moser, M., Ussar, S., Thievessen, I., Luber, C. A., Forner, F., Schmidt, S., Zanivan, S., Fassler, R., and Mann, M. (2008) SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell 134, 353-364 35. Geiger, T., Cox, J., Ostasiewicz, P., Wisniewski, J. R., and Mann, M. (2010) Super-SILAC mix for quantitative proteomics of human tumor tissue. Nat. Methods 7, 383-385 36. Rikova, K., Guo, A., Zeng, Q., Possemato, A., Yu, J., Haack, H., Nardone, J., Lee, K., Reeves, C., Li, Y., Hu, Y., Tan, Z., Stokes, M., Sullivan, L., Mitchell, J., Wetzel, R., Macneill, J., Ren, J. M., Yuan, J., Bakalarski, C. E., Villen, J., Kornhauser, J. M., Smith, B., Li, D., Zhou, X., Gygi, S. P., Gu, T. L., Polakiewicz, R. D., Rush, J., and Comb, M. J. (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 1190-1203 37. Wang, Y. T., Tsai, C. F., Hong, T. C., Tsou, C. C., Lin, P. Y., Pan, S. H., Hong, T. M., Yang, P. C., Sung, T. Y., Hsu, W. L., and Chen, Y. J. (2010) An informatics-assisted label-free quantitation strategy that depicts phosphoproteomic profiles in lung cancer cell invasion. J. Proteome Res. 9, 5582-5597 38. Cohen, P. (2002) The origins of protein phosphorylation. Nat. Cell Biol. 4, E127-130 39. Wu, R., Dephoure, N., Haas, W., Huttlin, E. L., Zhai, B., Sowa, M. E., and Gygi, S. P. (2011) Correct interpretation of comprehensive phosphorylation dynamics requires normalization by protein expression changes. Mol. Cell Proteomics 10, M111 009654 40. Zhang, X., Jin, Q. K., Carr, S. A., and Annan, R. S. (2002) N-Terminal peptide labeling strategy for incorporation of isotopic tags: a method for the determination of site-specific absolute phosphorylation stoichiometry. Rapid Commun. Mass Spectrom. 16, 2325-2332 41. Hegeman, A. D., Harms, A. C., Sussman, M. R., Bunner, A. E., and Harper, J. F. (2004) An isotope labeling strategy for quantifying the degree of phosphorylation at multiple sites in proteins. J. Am. Soc. Mass Spectrom. 15, 647-653 42. Pflieger, D., Junger, M. A., Muller, M., Rinner, O., Lee, H., Gehrig, P. M., Gstaiger, M., and Aebersold, R. (2008) Quantitative proteomic analysis of protein complexes: concurrent identification of interactors and their state of phosphorylation. Mol. Cell Proteomics 7, 326-346 43. Olsen, J. V., Vermeulen, M., Santamaria, A., Kumar, C., Miller, M. L., Jensen, L. J., Gnad, F., Cox, J., Jensen, T. S., Nigg, E. A., Brunak, S., and Mann, M. (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 3, ra3 44. Wu, R., Haas, W., Dephoure, N., Huttlin, E. L., Zhai, B., Sowa, M. E., and Gygi, S. P. (2011) A large-scale method to measure absolute protein phosphorylation stoichiometries. Nat. Methods 8, 677-683 45. Michalski, A., Cox, J., and Mann, M. (2011) More than 100,000 detectable peptide species elute in single shotgun proteomics runs but the majority is inaccessible to data-dependent LC-MS/MS. J. Proteome Res. 10, 1785-1793 46. Bensalah, K., Montorsi, F., and Shariat, S. F. (2007) Challenges of cancer biomarker profiling. Eur. Urol. 52, 1601-1609 47. Rifai, N., Gillette, M. A., and Carr, S. A. (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat. Biotechnol. 24, 971-983 48. Keshishian, H., Addona, T., Burgess, M., Kuhn, E., and Carr, S. A. (2007) Quantitative, multiplexed assays for low abundance proteins in plasma by targeted mass spectrometry and stable isotope dilution. Mol. Cell Proteomics 6, 2212-2229 49. Imamura, H., Sugiyama, N., Wakabayashi, M., and Ishihama, Y. (2014) Large-scale identification of phosphorylation sites for profiling protein kinase selectivity. J. Proteome Res. 13, 3410-3419 50. Han, C. L., Chien, C. W., Chen, W. C., Chen, Y. R., Wu, C. P., Li, H., and Chen, Y. J. (2008) A multiplexed quantitative strategy for membrane proteomics: opportunities for mining therapeutic targets for autosomal dominant polycystic kidney disease. Mol. Cell Proteomics 7, 1983-1997 51. Rappsilber, J., Mann, M., and Ishihama, Y. (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2, 1896-1906 52. Tsai, C. F., Hsu, C. C., Hung, J. N., Wang, Y. T., Choong, W. K., Zeng, M. Y., Lin, P. Y., Hong, R. W., Sung, T. Y., and Chen, Y. J. (2013) Sequential Phosphoproteomic Enrichment through Complementary Metal-Directed Immobilized Metal Ion Affinity Chromatography. Anal. Chem. 86, 685-693 53. Ishihama, Y., Rappsilber, J., Andersen, J. S., and Mann, M. (2002) Microcolumns with self-assembled particle frits for proteomics. J Chromatogr A 979, 233-239 54. Tsou, C. C., Tsai, C. F., Tsui, Y. H., Sudhir, P. R., Wang, Y. T., Chen, Y. J., Chen, J. Y., Sung, T. Y., and Hsu, W. L. (2010) IDEAL-Q, an automated tool for label-free quantitation analysis using an efficient peptide alignment approach and spectral data validation. Mol. Cell Proteomics 9, 131-144 55. Bendtsen, J. D., Nielsen, H., von Heijne, G., and Brunak, S. (2004) Improved prediction of signal peptides: SignalP 3.0. J. Mol. Biol. 340, 783-795 56. Schwartz, D., and Gygi, S. P. (2005) An iterative statistical approach to the identification of protein phosphorylation motifs from large-scale data sets. Nat. Biotechnol. 23, 1391-1398 57. Keshava Prasad, T. S., Goel, R., Kandasamy, K., Keerthikumar, S., Kumar, S., Mathivanan, S., Telikicherla, D., Raju, R., Shafreen, B., Venugopal, A., Balakrishnan, L., Marimuthu, A., Banerjee, S., Somanathan, D. S., Sebastian, A., Rani, S., Ray, S., Harrys Kishore, C. J., Kanth, S., Ahmed, M., Kashyap, M. K., Mohmood, R., Ramachandra, Y. L., Krishna, V., Rahiman, B. A., Mohan, S., Ranganathan, P., Ramabadran, S., Chaerkady, R., and Pandey, A. (2009) Human Protein Reference Database--2009 update. Nucleic Acids Res. 37, D767-772 58. Franceschini, A., Szklarczyk, D., Frankild, S., Kuhn, M., Simonovic, M., Roth, A., Lin, J., Minguez, P., Bork, P., von Mering, C., and Jensen, L. J. (2013) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 41, D808-815 59. Ficarro, S. B., Adelmant, G., Tomar, M. N., Zhang, Y., Cheng, V. J., and Marto, J. A. (2009) Magnetic bead processor for rapid evaluation and optimization of parameters for phosphopeptide enrichment. Anal. Chem. 81, 4566-4575 60. Zhou, W., Merrick, B. A., Khaledi, M. G., and Tomer, K. B. (2000) Detection and sequencing of phosphopeptides affinity bound to immobilized metal ion beads by matrix-assisted laser desorption/ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 11, 273-282 61. Lai, A. C., Tsai, C. F., Hsu, C. C., Sun, Y. N., and Chen, Y. J. (2012) Complementary Fe(3+)- and Ti(4+)-immobilized metal ion affinity chromatography for purification of acidic and basic phosphopeptides. Rapid Commun. Mass Spectrom. 26, 2186-2194 62. Kyte, J., and Doolittle, R. F. (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157, 105-132 63. Jemal, A., Thomas, A., Murray, T., and Thun, M. (2002) Cancer statistics, 2002. CA Cancer J Clin 52, 23-47 64. Pearson, R. G. (1963) Hard and Soft Acids and Bases. J. Am. Chem. Soc. 85, 3533-3539 65. Evers, A., Hancock, R. D., Martell, A. E., and Motekaitis, R. J. (1989) Metal ion recognition in ligands with negatively charged oxygen donor groups. Complexation of iron(III), gallium(III), indium(III), aluminum(III), and other highly charged metal ions. Inorg Chem 28, 2189-2195 66. Kosaka, T., Yamaki, E., Mogi, A., and Kuwano, H. (2011) Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small-cell lung cancer. J. Biomed. Biotechnol. 2011, 165214 67. Yatabe, Y. (2010) EGFR mutations and the terminal respiratory unit. Cancer Metastasis Rev. 29, 23-36 68. Engelman, J. A., and Janne, P. A. (2008) Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin. Cancer Res. 14, 2895-2899 69. Chang, T. H., Tsai, M. F., Su, K. Y., Wu, S. G., Huang, C. P., Yu, S. L., Yu, Y. L., Lan, C. C., Yang, C. H., Lin, S. B., Wu, C. P., Shih, J. Y., and Yang, P. C. (2011) Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am. J. Respir. Crit. Care Med. 183, 1071-1079 70. Koizumi, F., Shimoyama, T., Taguchi, F., Saijo, N., and Nishio, K. (2005) Establishment of a human non-small cell lung cancer cell line resistant to gefitinib. Int. J. Cancer 116, 36-44 71. Dinkel, H., Chica, C., Via, A., Gould, C. M., Jensen, L. J., Gibson, T. J., and Diella, F. (2011) Phospho.ELM: a database of phosphorylation sites--update 2011. Nucleic Acids Res. 39, D261-267 72. Hornbeck, P. V., Kornhauser, J. M., Tkachev, S., Zhang, B., Skrzypek, E., Murray, B., Latham, V., and Sullivan, M. (2012) PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 40, D261-270 73. Magrane, M., and Consortium, U. (2011) UniProt Knowledgebase: a hub of integrated protein data. Database (Oxford) 2011, bar009 74. Li, H., Xing, X., Ding, G., Li, Q., Wang, C., Xie, L., Zeng, R., and Li, Y. (2009) SysPTM: a systematic resource for proteomic research on post-translational modifications. Mol. Cell Proteomics 8, 1839-1849 75. Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C. M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A. J., Rogers, A. M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B. E., Cantley, L. C., and Janne, P. A. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043 76. Russo, G. L., Vandenberg, M. T., Yu, I. J., Bae, Y. S., Franza, B. R., Jr., and Marshak, D. R. (1992) Casein kinase II phosphorylates p34cdc2 kinase in G1 phase of the HeLa cell division cycle. J Biol Chem. 267, 20317-20325 77. Bloom, J., and Cross, F. R. (2007) Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol. 8, 149-160 78. Bouwman, P., and Jonkers, J. (2012) The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat. Rev. Cancer 12, 587-598 79. Holohan, C., Van Schaeybroeck, S., Longley, D. B., and Johnston, P. G. (2013) Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714-726 80. Flint, M. S., Kim, G., Hood, B. L., Bateman, N. W., Stewart, N. A., and Conrads, T. P. (2009) Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway. Psychoneuroendocrinology 34, 1533-1541 81. Zhang, Y., Ma, T., Yang, S., Xia, M., Xu, J., An, H., Yang, Y., and Li, S. (2011) High-mobility group A1 proteins enhance the expression of the oncogenic miR-222 in lung cancer cells. Mol Cell Biochem. 357, 363-371 82. Liau, S. S., and Whang, E. (2008) HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma. Clin. Cancer Res. 14, 1470-1477 83. Han, C. L., Chen, J. S., Chan, E. C., Wu, C. P., Yu, K. H., Chen, K. T., Tsou, C. C., Tsai, C. F., Chien, C. W., Kuo, Y. B., Lin, P. Y., Yu, J. S., Hsueh, C., Chen, M. C., Chan, C. C., Chang, Y. S., and Chen, Y. J. (2011) An informatics-assisted label-free approach for personalized tissue membrane proteomics: case study on colorectal cancer. Mol. Cell Proteomics 10, M110 003087 84. Quintana, L. F., Campistol, J. M., Alcolea, M. P., Banon-Maneus, E., Sol-Gonzalez, A., and Cutillas, P. R. (2009) Application of label-free quantitative peptidomics for the identification of urinary biomarkers of kidney chronic allograft dysfunction. Mol. Cell Proteomics 8, 1658-1673 85. Kim, H. J., Yu, M. H., Kim, H., Byun, J., and Lee, C. (2008) Noninvasive molecular biomarkers for the detection of colorectal cancer. BMB Rep 41, 685-692 86. Thompson, J. A., Grunert, F., and Zimmermann, W. (1991) Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J. Clin. Lab. Anal. 5, 344-366 87. Wanebo, H. J., Rao, B., Pinsky, C. M., Hoffman, R. G., Stearns, M., Schwartz, M. K., and Oettgen, H. F. (1978) Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. N. Engl. J. Med. 299, 448-451 88. Espina, V., Edmiston, K. H., Heiby, M., Pierobon, M., Sciro, M., Merritt, B., Banks, S., Deng, J., VanMeter, A. J., Geho, D. H., Pastore, L., Sennesh, J., Petricoin, E. F., 3rd, and Liotta, L. A. (2008) A portrait of tissue phosphoprotein stability in the clinical tissue procurement process. Mol. Cell Proteomics 7, 1998-2018 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57016 | - |
| dc.description.abstract | 蛋白質磷酸化在細胞訊息傳遞及功能調控上扮演關鍵角色。然而磷酸化含量的改變往往驅動與活化整個系統下游的訊息傳導路徑。過去幾年，磷酸化蛋白質體學技術已日趨成熟。但現今定量策略仍然無法有效區分所偵測到磷酸化的變化是來自於蛋白質含量的改變抑或是磷酸化程度上的改變。
在本論文第一部分中，我們首先發展一金屬導向序列純化金屬親和層析法來有效分離不同種類的磷酸化胜肽。此方法利用鎵金屬與磷酸根的親和能力相對較弱，可將高達99.4%的具有更多負電荷的多磷酸化胜肽純化出來。此外，藉由與磷酸化官能基親和能力不同的鎵與鐵兩種金屬離子，可有效地將酸性 (72%)、鹼性 (85%) 以及帶有脯氨酸(Proline)(79%) 的這些不同蛋白激酶受質的酶磷酸化胜肽分別在第一維鎵金屬以及第二維的鐵金屬親和層析法分離出來，利用此方法有效的降低樣品複雜度以提升鑑定到與肺癌相關訊息傳導路徑蛋白的數量。 在論文第二部分中，為了能夠分析單一細胞的磷酸化程度，我們發展一以特定序列標靶導向的蛋白質體定量平台。至今，此平台為第一個可用來系統性的針對單一人類蛋白質體進行磷酸化程度定量分析。藉由蛋白激酶與其受質的反應專一性，從僅僅50微克的細胞量中，我們可定量到上百條低含量的酪胺酸的磷酸化胜肽。利用此特定序列標靶導向的蛋白質體定量平台，我們找到幾個蛋白，其磷酸化程度的改變可能與肺癌抗藥機制有關。此外，透過建立EGFR和CK2兩個蛋白激酶的訊息網路，我們可以從中找出具有潛力的肺癌抗藥標靶蛋白。 在論文最後一部分中，我們發展了一高解析度的掃描頻率多重反應監測質譜法(Enhanced Duty Cycle Multiple Reaction Monitoring,EDC-MRMHR) ，可以進一步驗證膜蛋白以及磷酸化位點進行準確定量分析。藉由增強在飛行式質譜其掃描頻率週期 (Enhanced Duty Cycle) ，針對碎片離子偵測靈敏度提高了10倍。此定量方法提供了好的定量精準度以及線性範圍(R2 =0.998, CV<20%)。我們利用此方法於10位大腸直腸癌病患中驗證潛在的癌症生物標記。其結果與傳統利用抗體驗證的方法一致。我們期待此論文中所發展出新的分析策略在將來可有效地應用在不同疾病的磷酸化蛋白質體學的分析。 | zh_TW |
| dc.description.abstract | Measurement on the phosphorylation event is often used as indicator for signaling pathway activation. Despite that analytical approaches for phosphoproteomics have matured within the past decade, enrichment and detection towards comprehensive phosphoproteomic profiling remain to the improvement. In addition, the functional role of aberrant protein phosphorylation in cancer-related cell signaling is impacted by its fractional stoichiometry. However, the interpretation of quantitative phosphoproteomics studies by conventional approaches is complicated because each differential phosphorylation event can be associated with a change either in phosphorylation stoichiometry or in protein abundance. Most of the current quantitative strategies are not able to differentiate such changes.
In this thesis, we developed multiple approaches to address the above issues. To overcome the complexity of the human phosphoproteome, in the first part of thesis, we introduced a tip based immobilized metal ion affinity chromatography (Ga3+-Fe3+-IMAC) for sequential enrichment of heterogeneous phosphopeptides. Based on the weak binding affinity between Ga3+ and phosphopeptides, the Ga3+-IMAC successfully enhanced the enrichment of multiple phosphopeptides, which carried more negative charges; 99.4% were enriched by the first Ga3+-IMAC. Acidophilic phosphorylation sites were predominately enriched in the first Ga3+-IMAC (72%), while Pro-directed (85%) and basophilic (79%) phosphorylation sites were enriched in the second Fe3+-IMAC. This strategy provided complementary mapping of different kinase substrates in multiple cellular pathways related to cancer invasion and metastasis of lung cancer. To measure the phosphorylation stoichiometry of single cell status, in the second part of the thesis, we have developed a motif-targeting quantitative proteomic approach. To our knowledge, this method is the first large-scale approach to provide system-wide phosphorylation stoichiometry of a single-state human proteome. In addition, this assay offers the advantage of kinase-targeted complexity reduction for deeper phosphoproteome analysis; hundreds of tyrosine phosphopeptide could be detected from only 50 μg lysates. For the application of quantitative measurement on the drug-resistant and sensitive lung cancer cell line, this motif-targeting approach differentiates drug resistance-associated changes in phosphorylation stoichiometry from those at the protein level in lung cancer, which also suggested potential druggable target protein in the EGFR- and CK2-centred kinase-substrate network. In the last part of thesis, we developed a multiple reaction monitoring (MRM) based quantitative platform, EDC-MRMHR, as an alternative method for verification of site-specific alteration of phosphoprotein, especially for antibody | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:33:00Z (GMT). No. of bitstreams: 1 ntu-103-D99223206-1.pdf: 5860620 bytes, checksum: af6d555fa30bb17933d773f709f73967 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員會審定書
謝誌 中文摘要(I) 英文摘要(III) 目錄 ((VI) CHAPTER 1 Introduction 1.1 Significance of protein phosphorylation (p.1) 1.2 The basics of MS-based phosphoproteomics analyses (p.2) 1.3 Enrichment of phosphopeptides by affinity purification (p.2) 1.4 Quantitative phosphoproteomics (p.6) 1.5 Current challenge in phosphoproteomics analysis (p.10) 1.6 Objective (p.12) CHAPTER 2 Material and method 2.1 Chemicals and material (p.15) 2.2 Sample preparation (p.15) 2.2.1 Standard peptide mixture (p.15) 2.2.2 Total protein extraction from Raji B cell (p.16) 2.2.3 Total protein extraction from lung cancer cell (p.16) 2.2.4 Total protein extraction from lung cancer tissue (p.16) 2.2.5 Membrane protein extraction from colon cancer tissue (p.17) 2.3 Dephosphorylation by (thermosensitive alkaline phosphatase) TSAP (p.18) 2.4 Tryptic digestion of cell lysate (p.18) 2.4.1 Gel-assisted digestion of total protein from cell lysate (p.18) 2.4.2 Gel-assisted digestion of total protein from lung cancer tissue (p.18) 2.4.3 Gel-assisted digestion of membrane protein from colon tissue (p.19) 2.4.4 Molecular weight filter assisted tryptic digestion of total protein from cell lysate (p.20) 2.5 Tip-based pH/acid controlled immobilized metal ion affinity chromatography (IMAC) (p.20) 2.5.1 Fe3+-IMAC and Ga3+-IMAC (p.20) 2.5.2 Ga3+-Fe3+-IMAC (p.21) 2.6 Stable isotope dimethyl labeling (p.21) 2.7 Kinase reaction (p.21) 2.8 MALDI-TOF MS Analysis (p.22) 2.9 LC-MS/MS analysis (p.22) 2.9.1 Phosphopeptides analysis by TripleTOF 5600 (p.22) 2.9.2 Membrane peptides analysis by Waters Synapt HDMS (p.23) 2.10 Data processing and protein identification (p.24) 2.11Quantitative analysis by IDEAL-Q (p.25) 2.12 Protein annotation (p.25) 2.13 Motif analysis (p.26) 2.14 Western blotting (p.26) 2.15 Real-time RT-PCR (p.27) CHAPTER 3 Result and discussion 3.1 Methodology development for sequential phosphoproteomic enrichment (p.28) 3.1.1 Complementary enrichment via Ga3+-IMAC and Fe3+-IMAC (p.28) 3.1.2 Highly complementary identification via sequential IMAC increases phosphoproteomic profiling coverage (p.29) 3.1.3 Sequence- and motif-directed separation via sequential IMAC (p.32) 3.1.4 Application of sequential Ga3+-Fe3+-IMAC in human lung cancer tissue analysis (p.33) 3.1.5 Proposed mechanism of Ga3+-Fe3+-IMAC for effective fractionation of heterogeneous phosphopeptides (p.36) 3.2 Motif-targeting isotopic quantitative proteomics for absolute phosphorylation stoichiometry measurement (p.39) 3.2.1 Workflow and experimental design of motif-targeting isotopic quantitative approach (p.39) 3.2.2 Evaluation of quantitation precision and reproducibility of phosphorylation stoichiometry measurement (p.40) 3.2.3 Differential phosphorylation stoichiometry profiles in drug sensitive and resistance cell model (p.40) 3.2.4 Identification of potential drug target associated EGFR-TKI resistance in NSCLC (p.43) 3.2.5 Limitation of motif targeting quantitative approach (p.46) 3.3 An informatics-assisted label-free quantitation strategy EDC-MRMHR for high-speed personalized proteomic profiling and target protein verification (p.48) 3.3.1 Workflow and experimental design (p.48) 3.3.2 Performance of elution time alignment and cross-assignment between long and short LC-MS/MS (p.50) 3.3.3 The performance of EDC-MRMHR (p.53) 3.3.4 Application on personalized human tissue analysis (p.54) CHAPTER 4 Conclusion and future perspective (p.57) CHAPTER 5 Reference (p.60) CHAPTER 6 Figures (p.72) CHAPTER 7 Tables (p.104) | |
| dc.language.iso | en | |
| dc.subject | 磷酸化蛋白體 | zh_TW |
| dc.subject | 高解析度的掃描頻率多重反應監測質譜法 | zh_TW |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | 大腸癌 | zh_TW |
| dc.subject | 磷酸化程度 | zh_TW |
| dc.subject | 金屬親和層析法 | zh_TW |
| dc.subject | colon cancer | en |
| dc.subject | IMAC | en |
| dc.subject | phosphorylation stoichiometry | en |
| dc.subject | EDC-MRMHR | en |
| dc.subject | lung cancer | en |
| dc.subject | phosphoproteomics | en |
| dc.title | 以金屬親和層析法結合質譜技術分析磷酸化蛋白體 | zh_TW |
| dc.title | Qualitative and Quantitative IMAC-based Strategy Development toward Comprehensive Phosphoproteomics Analysis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 石濱泰(Yasushi Ishihama),邱繼輝(Kay-Hooi Khoo),戴桓青(Hwan-Ching Tai),林頌然(Sung-Jan Lin),潘思樺(Szu-Hua Pan) | |
| dc.subject.keyword | 磷酸化蛋白體,金屬親和層析法,磷酸化程度,高解析度的掃描頻率多重反應監測質譜法,肺癌,大腸癌, | zh_TW |
| dc.subject.keyword | phosphoproteomics,IMAC,phosphorylation stoichiometry,EDC-MRMHR,lung cancer,colon cancer, | en |
| dc.relation.page | 109 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-05 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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