多數的蛋白質皆可被轉變成具有細胞毒性的纖維化蛋白質。然而在轉變的過程中，通常需要高濃度的蛋白質、劇烈的攪動或纖維化蛋白種子。再者纖維化蛋白質所引起細胞凋亡的機制也未被充分研究。在口蹄疫病毒VP3鞘蛋白的研究中，我們發現了一種可將球型蛋白質轉變成纖維化蛋白質的管柱製程。因此，我們進一步研究這種可將球型蛋白質轉變成纖維化蛋白質的管柱製程的作用機轉。利用此製程可將球型牛血清白蛋白（G-BSA）轉變成纖維化牛血清白蛋白（F-BSA），並進一步探討纖維化蛋白質引起細胞凋亡的訊息傳遞路徑。我們發現利用Superdex-200管柱且在陰離子或兩性離子清潔劑的存在下可將球型牛血清白蛋白轉變成纖維化牛血清白蛋白。若考慮形成纖維化蛋白的要求，則是管柱中的樹脂孔洞大小比樹脂材質更為重要。纖維化牛血清白蛋白可引起BHK-21與T47D細胞的凋亡。細胞預先處理整合素的抗體後，則纖維化牛血清白蛋白引起的細胞凋亡會被抑制。纖維化牛血清白蛋白可與整合素結合，並使得FAK，Akt和GSK-3β去磷酸化。因此，纖維化蛋白質所引起細胞凋亡的機制是藉由調控Integrin/FAK/Akt/GSK-3β途徑。再者，我們也利用此管柱製程將具有訊息傳遞功能的球型纖粘蛋白(G-FN)轉變成纖維化纖粘蛋白(F-FN)。球型纖粘蛋白與纖維化纖粘蛋白皆可以和整合素結合，但纖維化纖粘蛋白所引起的細胞效應與球型纖粘蛋白不同，球型纖粘蛋白會造成細胞增生，而纖維化纖粘蛋白反而會引起細胞凋亡。纖維化纖粘蛋白會引起細胞骨架的重組和應力纖維的形成。纖維化纖粘蛋白也會引起SHP-2、RhoA/ROCK、肌絲蛋白的活化及FAK，Akt和GSK-3β的去磷酸化。纖維化纖粘蛋白所引起的細胞凋亡可被整合素α5β1抗體、整合素β1抗體、SHP-2抑制劑、SHP-2 AS-ODN、Rho激脢抑制劑及ROCK顯性抑制質體所抑制。再者，我們也發現了纖維化纖粘蛋白可抑制癌細胞（如：卵巢癌細胞SKOV-3和人類乳癌細胞MCF-7）的生長。我們的結果證明了纖維化纖粘蛋白為一種可以引發細胞凋亡的物質，其可以促使訊息傳導物質如Akt/GSK-3β去活化，並藉由SHP-2、RhoA/ROCK、肌絲蛋白的活化造成細胞應力纖維形成且引起細胞凋亡。因此，本論文的重要研究成果為藉由纖維化纖粘蛋白的研究可以瞭解纖維化蛋白的致病性，解析纖維化蛋白誘發凋亡機轉並作為細胞凋亡現象產生障礙的疾病（如癌症）治療上之應用。

Numerous proteins can be converted to amyloid-like fibrils to increase cytotoxicity and induce apoptosis, but the methods generally require a high concentration of protein, vigorous shaking, or fibril seed. As well, the detailed mechanism of the cytotoxic effects is not well characterized. We utilized a column process to refold rVP3 of foot-and-mouth disease virus (FMDV) and found that this column process might convert globular proteins to fibrillar proteins. We thus investigated the mechanism of forming fibrillar proteins by this column process. We used globular bovine serum albumin (BSA) as a model protein to verify the properties of the fibrillar protein, investigated its cellular effects and studied the signaling cascade induced by the fibrillar protein. It was found that BSA was induced to become fibril by a novel process involving Superdex-200 column chromatography in the presence of anionic or zwittergenic detergent(s). The column pore size was more important than column matrix composite in fibril formation. The fibrillar BSA induced apoptosis in BHK-21 cell as well as breast cancer cell line T47D. Pre-treating cells with anti-integrin antibodies blocked the apoptotic effect. Fibrillar BSA, but not globular BSA, bound to integrin, dephosphorylated focal adhesion kinase (FAK), Akt and glycogen synthase kinase-3β (GSK-3β). Furthermore, we also converted globular fibronectin (G-FN) into fibrillar fibronectin (F-FN) by the same column process. Both G-FN and F-FN interacted with integrin a5β1, but unlike G-FN which induced proliferation, F-FN treatment resulted in apoptosis. F-FN induced stress fiber formation via cytoskeleton rearrangement. The effects of F-FN were associated with signaling events such as activation of SHP-2, RhoA/ROCK and filamin A as well as dephosphorylation of FAK, Akt, and GSK-3β. Moreover, the apoptotic effect of F-FN was blocked by pretreatment of cells with antibodies against integrin a5β1 and integrin β1, respectivley. It was also decreased by SHP-2 inhibitor, SHP-2 antisense oligodeoxynucleotide, ROCK inhibitor or dominant negative plasmid. Pharmacological studies revealed that F-FN was effective in inhibiting the survival of SKOV-3 and MCF-7 cancer cells. These results suggest that F-FN may deactivate downstream Akt/GSK-3β signaling transduction pathways, induce stress fiber formation via SHP-2, RhoA and filamin. Therefore, the most important finding in this thesis is that via understanding the pathogenesis of amyloid-like fibrils and elucidating the mechanism of fibrillar protein-induced cytotoxicity, it is feasible for development of better therapeutic agents for apoptosis-impaired diseases, such as cancer.

Acharya, R., Fry, E., Stuart, D., Fox, G., Rowlands, D. and Brown, F. The three-dimensional structure of foot-and-mouth disease virus at 2.9 A resolution. Nature 337(6209): 709-716, 1989.
Ahmad, M. F., Ramakrishna, T., Raman, B. and Rao Ch, M. Fibrillogenic and non-fibrillogenic ensembles of SDS-bound human alpha-synuclein. J Mol Biol 364(5): 1061-1072, 2006.
Alexandersen, S., Zhang, Z., Donaldson, A. I. and Garland, A. J. The pathogenesis and diagnosis of foot-and-mouth disease. J Comp Pathol 129(1): 1-36, 2003.
Ambesi, A., Klein, R. M., Pumiglia, K. M. and McKeown-Longo, P. J. Anastellin, a fragment of the first type III repeat of fibronectin, inhibits extracellular signal-regulated kinase and causes G(1) arrest in human microvessel endothelial cells. Cancer Res 65(1): 148-156, 2005.
Arnold, T. and Linke, D. Phase separation in the isolation and purification of membrane proteins. Biotechniques 43(4): 427-430, 432, 434 passim, 2007.
Arthur, W. T., Noren, N. K. and Burridge, K. Regulation of Rho family GTPases by cell-cell and cell-matrix adhesion. Biol Res 35(2): 239-246, 2002.
Azakami, H., Mukai, A. and Kato, A. Role of amyloid type cross beta-structure in the formation of soluble aggregate and gel in heat-induced ovalbumin. J Agric Food Chem 53(4): 1254-1257, 2005.
Belsham, G. J. Distinctive features of foot-and-mouth disease virus, a member of the picornavirus family; aspects of virus protein synthesis, protein processing and structure. Prog Biophys Mol Biol 60(3): 241-260, 1993.
Benetti, L., Munger, J. and Roizman, B. The herpes simplex virus 1 US3 protein kinase blocks caspase-dependent double cleavage and activation of the proapoptotic protein BAD. J Virol 77(11): 6567-6573, 2003.
Bennett, A. M., Hausdorff, S. F., O'Reilly, A. M., Freeman, R. M. and Neel, B. G. Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol Cell Biol 16(3): 1189-1202, 1996.
Berinstein, A., Roivainen, M., Hovi, T., Mason, P. W. and Baxt, B. Antibodies to the vitronectin receptor (integrin alpha V beta 3) inhibit binding and infection of foot-and-mouth disease virus to cultured cells. J Virol 69(4): 2664-2666, 1995.
Billen, L. P., Shamas-Din, A. and Andrews, D. W. Bid: a Bax-like BH3 protein. Oncogene 27 Suppl 1: S93-104, 2008.
Bouma, B., Kroon-Batenburg, L. M., Wu, Y. P., Brunjes, B., Posthuma, G., Kranenburg, O., de Groot, P. G., Voest, E. E. and Gebbink, M. F. Glycation induces formation of amyloid cross-beta structure in albumin. J Biol Chem 278(43): 41810-41819, 2003.
Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J. and Greenberg, M. E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6): 857-868, 1999.
Bucciantini, M., Calloni, G., Chiti, F., Formigli, L., Nosi, D., Dobson, C. M. and Stefani, M. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem 279(30): 31374-31382, 2004.
Burridge, K., Chrzanowska-Wodnicka, M. and Zhong, C. Focal adhesion assembly. Trends Cell Biol 7(9): 342-347, 1997.
Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E., Frisch, S. and Reed, J. C. Regulation of cell death protease caspase-9 by phosphorylation. Science 282(5392): 1318-1321, 1998.
Chauhan, D., Pandey, P., Hideshima, T., Treon, S., Raje, N., Davies, F. E., Shima, Y., Tai, Y. T., Rosen, S., Avraham, S., Kharbanda, S. and Anderson, K. C. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem 275(36): 27845-27850, 2000.
Chen, H. C., Appeddu, P. A., Parsons, J. T., Hildebrand, J. D., Schaller, M. D. and Guan, J. L. Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem 270(28): 16995-16999, 1995.
Chinnaiyan, A. M., O'Rourke, K., Tewari, M. and Dixit, V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81(4): 505-512, 1995.
Chow, M. K., Ellisdon, A. M., Cabrita, L. D. and Bottomley, S. P. Purification of polyglutamine proteins. Methods Enzymol 413: 1-19, 2006.
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. and Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559): 785-789, 1995.
Danen, E. H. Integrins: regulators of tissue function and cancer progression. Curr Pharm Des 11(7): 881-891, 2005.
Danzer, K. M., Haasen, D., Karow, A. R., Moussaud, S., Habeck, M., Giese, A., Kretzschmar, H., Hengerer, B. and Kostka, M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27(34): 9220-9232, 2007.
Darenfed, H., Dayanandan, B., Zhang, T., Hsieh, S. H., Fournier, A. E. and Mandato, C. A. Molecular characterization of the effects of Y-27632. Cell Motil Cytoskeleton 64(2): 97-109, 2007.
Dedhar, S. and Hannigan, G. E. Integrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr Opin Cell Biol 8(5): 657-669, 1996.
DeMali, K. A., Wennerberg, K. and Burridge, K. Integrin signaling to the actin cytoskeleton. Curr Opin Cell Biol 15(5): 572-582, 2003.
Engel, M. F., Khemtemourian, L., Kleijer, C. C., Meeldijk, H. J., Jacobs, J., Verkleij, A. J., de Kruijff, B., Killian, J. A. and Hoppener, J. W. Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proc Natl Acad Sci U S A 105(16): 6033-6038, 2008.
Etienne-Manneville, S. and Hall, A. Rho GTPases in cell biology. Nature 420(6916): 629-635, 2002.
Feng, G. S. and Pawson, T. Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction. Trends Genet 10(2): 54-58, 1994.
Fornaro, M., Plescia, J., Chheang, S., Tallini, G., Zhu, Y. M., King, M., Altieri, D. C. and Languino, L. R. Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem 278(50): 50402-50411, 2003.
Gharibyan, A. L., Zamotin, V., Yanamandra, K., Moskaleva, O. S., Margulis, B. A., Kostanyan, I. A. and Morozova-Roche, L. A. Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways. J Mol Biol 365(5): 1337-1349, 2007.
Ginsberg, M. H., Partridge, A. and Shattil, S. J. Integrin regulation. Curr Opin Cell Biol 17(5): 509-516, 2005.
Glabe, C. G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 27(4): 570-575, 2006.
Glabe, C. G. Structural classification of toxic amyloid oligomers. J Biol Chem 283(44): 29639-29643, 2008.
Glass, E. J. and Millar, P. Bovine T cells preferentially recognize non-viral spacer epitopes in a putative FMDV vaccinal peptide. Vaccine 13(2): 225-229, 1995.
Goda, S., Takano, K., Yamagata, Y., Nagata, R., Akutsu, H., Maki, S., Namba, K. and Yutani, K. Amyloid protofilament formation of hen egg lysozyme in highly concentrated ethanol solution. Protein Sci 9(2): 369-375, 2000.
Gogvadze, V., Orrenius, S. and Zhivotovsky, B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim Biophys Acta 1757(5-6): 639-647, 2006.
Hedman, K., Johansson, S., Vartio, T., Kjellen, L., Vaheri, A. and Hook, M. Structure of the pericellular matrix: association of heparan and chondroitin sulfates with fibronectin-procollagen fibers. Cell 28(3): 663-671, 1982.
Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y. and Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12): 988-1004, 2005.
Hetz, C., Bernasconi, P., Fisher, J., Lee, A. H., Bassik, M. C., Antonsson, B., Brandt, G. S., Iwakoshi, N. N., Schinzel, A., Glimcher, L. H. and Korsmeyer, S. J. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312(5773): 572-576, 2006.
Hynes, R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69(1): 11-25, 1992.
Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110(6): 673-687, 2002.
Ishizaki, T., Naito, M., Fujisawa, K., Maekawa, M., Watanabe, N., Saito, Y. and Narumiya, S. p160ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett 404(2-3): 118-124, 1997.
Jackson, T., Blakemore, W., Newman, J. W., Knowles, N. J., Mould, A. P., Humphries, M. J. and King, A. M. Foot-and-mouth disease virus is a ligand for the high-affinity binding conformation of integrin alpha5beta1: influence of the leucine residue within the RGDL motif on selectivity of integrin binding. J Gen Virol 81(Pt 5): 1383-1391, 2000.
Jackson, T., Mould, A. P., Sheppard, D. and King, A. M. Integrin alphavbeta1 is a receptor for foot-and-mouth disease virus. J Virol 76(3): 935-941, 2002.
Jackson, T., Sheppard, D., Denyer, M., Blakemore, W. and King, A. M. The epithelial integrin alphavbeta6 is a receptor for foot-and-mouth disease virus. J Virol 74(11): 4949-4956, 2000.
Jiang, X. and Wang, X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 275(40): 31199-31203, 2000.
Kamarajan, P. and Kapila, Y. L. An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. Apoptosis 12(12): 2221-2231, 2007.
Kapila, Y. L., Kapila, S. and Johnson, P. W. Fibronectin and fibronectin fragments modulate the expression of proteinases and proteinase inhibitors in human periodontal ligament cells. Matrix Biol 15(4): 251-261, 1996.
King, W. G., Mattaliano, M. D., Chan, T. O., Tsichlis, P. N. and Brugge, J. S. Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation. Mol Cell Biol 17(8): 4406-4418, 1997.
Kirkland, R. A. and Franklin, J. L. Bax, reactive oxygen, and cytochrome c release in neuronal apoptosis. Antioxid Redox Signal 5(5): 589-596, 2003.
Kitson, J. D., McCahon, D. and Belsham, G. J. Sequence analysis of monoclonal antibody resistant mutants of type O foot and mouth disease virus: evidence for the involvement of the three surface exposed capsid proteins in four antigenic sites. Virology 179(1): 26-34, 1990.
Kleid, D. G., Yansura, D., Small, B., Dowbenko, D., Moore, D. M., Grubman, M. J., McKercher, P. D., Morgan, D. O., Robertson, B. H. and Bachrach, H. L. Cloned viral protein vaccine for foot-and-mouth disease: responses in cattle and swine. Science 214(4525): 1125-1129, 1981.
Klunk, W. E., Jacob, R. F. and Mason, R. P. Quantifying amyloid by congo red spectral shift assay. Methods Enzymol 309: 285-305, 1999.
Kranenburg, O., Kroon-Batenburg, L. M., Reijerkerk, A., Wu, Y. P., Voest, E. E. and Gebbink, M. F. Recombinant endostatin forms amyloid fibrils that bind and are cytotoxic to murine neuroblastoma cells in vitro. FEBS Lett 539(1-3): 149-155, 2003.
Kreplak, L. and Aebi, U. From the polymorphism of amyloid fibrils to their assembly mechanism and cytotoxicity. Adv Protein Chem 73: 217-233, 2006.
Kruidering, M. and Evan, G. I. Caspase-8 in apoptosis: the beginning of "the end"? IUBMB Life 50(2): 85-90, 2000.
Kuwada, S. K. and Li, X. Integrin alpha5/beta1 mediates fibronectin-dependent epithelial cell proliferation through epidermal growth factor receptor activation. Mol Biol Cell 11(7): 2485-2496, 2000.
Lacalle, R. A., Mira, E., Gomez-Mouton, C., Jimenez-Baranda, S., Martinez, A. C. and Manes, S. Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation. J Cell Biol 157(2): 277-289, 2002.
LeVine, H., 3rd. Quantification of beta-sheet amyloid fibril structures with thioflavin T. Methods Enzymol 309: 274-284, 1999.
Ling, Y., Maile, L. A. and Clemmons, D. R. Tyrosine phosphorylation of the beta3-subunit of the alphaVbeta3 integrin is required for embrane association of the tyrosine phosphatase SHP-2 and its further recruitment to the insulin-like growth factor I receptor. Mol Endocrinol 17(9): 1824-1833, 2003.
Lobley, A., Whitmore, L. and Wallace, B. A. DICHROWEB: an interactive website for the analysis of protein secondary structure from circular dichroism spectra. Bioinformatics 18(1): 211-212, 2002.
Logan, D., Abu-Ghazaleh, R., Blakemore, W., Curry, S., Jackson, T., King, A., Lea, S., Lewis, R., Newman, J., Parry, N. and et al. Structure of a major immunogenic site on foot-and-mouth disease virus. Nature 362(6420): 566-568, 1993.
Lui, W. Y., Lee, W. M. and Cheng, C. Y. Rho GTPases and spermatogenesis. Biochim Biophys Acta 1593(2-3): 121-129, 2003.
Luo, H. R., Hattori, H., Hossain, M. A., Hester, L., Huang, Y., Lee-Kwon, W., Donowitz, M., Nagata, E. and Snyder, S. H. Akt as a mediator of cell death. Proc Natl Acad Sci U S A 100(20): 11712-11717, 2003.
Mannell, H., Hellwig, N., Gloe, T., Plank, C., Sohn, H. Y., Groesser, L., Walzog, B., Pohl, U. and Krotz, F. Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo. J Vasc Res 45(2): 153-163, 2008.
Martin, D., Salinas, M., Lopez-Valdaliso, R., Serrano, E., Recuero, M. and Cuadrado, A. Effect of the Alzheimer amyloid fragment Abeta(25-35) on Akt/PKB kinase and survival of PC12 cells. J Neurochem 78(5): 1000-1008, 2001.
Mason, P. W., Rieder, E. and Baxt, B. RGD sequence of foot-and-mouth disease virus is essential for infecting cells via the natural receptor but can be bypassed by an antibody-dependent enhancement pathway. Proc Natl Acad Sci U S A 91(5): 1932-1936, 1994.
McCahon, D., Crowther, J. R., Belsham, G. J., Kitson, J. D., Duchesne, M., Have, P., Meloen, R. H., Morgan, D. O. and De Simone, F. Evidence for at least four antigenic sites on type O foot-and-mouth disease virus involved in neutralization; identification by single and multiple site monoclonal antibody-resistant mutants. J Gen Virol 70 ( Pt 3): 639-645, 1989.
Milarski, K. L. and Saltiel, A. R. Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem 269(33): 21239-21243, 1994.
Mitra, S. K. and Schlaepfer, D. D. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18(5): 516-523, 2006.
Miyamoto, S., Akiyama, S. K. and Yamada, K. M. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 267(5199): 883-885, 1995.
Montgomery, A. M., Reisfeld, R. A. and Cheresh, D. A. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci U S A 91(19): 8856-8860, 1994.
Morla, A., Zhang, Z. and Ruoslahti, E. Superfibronectin is a functionally distinct form of fibronectin. Nature 367(6459): 193-196, 1994.
Nakagawa, O., Fujisawa, K., Ishizaki, T., Saito, Y., Nakao, K. and Narumiya, S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392(2): 189-193, 1996.
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A. and Yuan, J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765): 98-103, 2000.
Narumiya, S., Tanji, M. and Ishizaki, T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28(1-2): 65-76, 2009.
Ndozangue-Touriguine, O., Hamelin, J. and Breard, J. Cytoskeleton and apoptosis. Biochem Pharmacol 76(1): 11-18, 2008.
Necula, M., Chirita, C. N. and Kuret, J. Rapid anionic micelle-mediated alpha-synuclein fibrillization in vitro. J Biol Chem 278(47): 46674-46680, 2003.
Neel, B. G. and Tonks, N. K. Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol 9(2): 193-204, 1997.
Neff, S., Sa-Carvalho, D., Rieder, E., Mason, P. W., Blystone, S. D., Brown, E. J. and Baxt, B. Foot-and-mouth disease virus virulent for cattle utilizes the integrin alpha(v)beta3 as its receptor. J Virol 72(5): 3587-3594, 1998.
Nelson, R. and Eisenberg, D. Structural models of amyloid-like fibrils. Adv Protein Chem 73: 235-282, 2006.
Nobes, C. D. and Hall, A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81(1): 53-62, 1995.
O'Toole, T. E., Katagiri, Y., Faull, R. J., Peter, K., Tamura, R., Quaranta, V., Loftus, J. C., Shattil, S. J. and Ginsberg, M. H. Integrin cytoplasmic domains mediate inside-out signal transduction. J Cell Biol 124(6): 1047-1059, 1994.
Ohnishi, S. and Takano, K. Amyloid fibrils from the viewpoint of protein folding. Cell Mol Life Sci 61(5): 511-524, 2004.
Pankov, R. and Yamada, K. M. Fibronectin at a glance. J Cell Sci 115(Pt 20): 3861-3863, 2002.
Park, C. C., Zhang, H., Pallavicini, M., Gray, J. W., Baehner, F., Park, C. J. and Bissell, M. J. Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Res 66(3): 1526-1535, 2006.
Pellenc, D., Berry, H. and Gallet, O. Adsorption-induced fibronectin aggregation and fibrillogenesis. J Colloid Interface Sci 298(1): 132-144, 2006.
Peng, J. M., Liang, S. M. and Liang, C. M. VP1 of foot-and-mouth disease virus induces apoptosis via the Akt signaling pathway. J Biol Chem 279(50): 52168-52174, 2004.
Pertinhez, T. A., Bouchard, M., Smith, R. A., Dobson, C. M. and Smith, L. J. Stimulation and inhibition of fibril formation by a peptide in the presence of different concentrations of SDS. FEBS Lett 529(2-3): 193-197, 2002.
Peters, D. M., Portz, L. M., Fullenwider, J. and Mosher, D. F. Co-assembly of plasma and cellular fibronectins into fibrils in human fibroblast cultures. J Cell Biol 111(1): 249-256, 1990.
Petratos, S., Li, Q. X., George, A. J., Hou, X., Kerr, M. L., Unabia, S. E., Hatzinisiriou, I., Maksel, D., Aguilar, M. I. and Small, D. H. The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131(Pt 1): 90-108, 2008.
Plow, E. F., Haas, T. A., Zhang, L., Loftus, J. and Smith, J. W. Ligand binding to integrins. J Biol Chem 275(29): 21785-21788, 2000.
Porter, A. G. and Janicke, R. U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2): 99-104, 1999.
Qahwash, I., Weiland, K. L., Lu, Y., Sarver, R. W., Kletzien, R. F. and Yan, R. Identification of a mutant amyloid peptide that predominantly forms neurotoxic protofibrillar aggregates. J Biol Chem 278(25): 23187-23195, 2003.
Raines, E. W. The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int J Exp Pathol 81(3): 173-182, 2000.
Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D. and Hall, A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70(3): 401-410, 1992.
Ruoslahti, E. and Pierschbacher, M. D. New perspectives in cell adhesion: RGD and integrins. Science 238(4826): 491-497, 1987.
Sagis, L. M., Veerman, C. and van der Linden, E. Mesoscopic properties of semiflexible amyloid fibrils. Langmuir 20(3): 924-927, 2004.
Saiki, M., Konakahara, T. and Morii, H. Interaction-based evaluation of the propensity for amyloid formation with cross-beta structure. Biochem Biophys Res Commun 343(4): 1262-1271, 2006.
Saxton, T. M., Henkemeyer, M., Gasca, S., Shen, R., Rossi, D. J., Shalaby, F., Feng, G. S. and Pawson, T. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J 16(9): 2352-2364, 1997.
Schaller, M. D., Otey, C. A., Hildebrand, J. D. and Parsons, J. T. Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. J Cell Biol 130(5): 1181-1187, 1995.
Schneller, M., Vuori, K. and Ruoslahti, E. Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. Embo J 16(18): 5600-5607, 1997.
Seyb, K. I., Ansar, S., Bean, J. and Michaelis, M. L. beta-Amyloid and endoplasmic reticulum stress responses in primary neurons: effects of drugs that interact with the cytoskeleton. J Mol Neurosci 28(2): 111-123, 2006.
Shea, T. B. and Ortiz, D. 17 beta-estradiol alleviates synergistic oxidative stress resulting from folate deprivation and amyloid-beta treatment. J Alzheimers Dis 5(4): 323-327, 2003.
Shimizu, S., Narita, M. and Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399(6735): 483-487, 1999.
Slee, E. A., Harte, M. T., Kluck, R. M., Wolf, B. B., Casiano, C. A., Newmeyer, D. D., Wang, H. G., Reed, J. C., Nicholson, D. W., Alnemri, E. S., Green, D. R. and Martin, S. J. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144(2): 281-292, 1999.
Somanath, P. R., Razorenova, O. V., Chen, J. and Byzova, T. V. Akt1 in endothelial cell and angiogenesis. Cell Cycle 5(5): 512-518, 2006.
Springer, T. A. Adhesion receptors of the immune system. Nature 346(6283): 425-434, 1990.
Stathopulos, P. B., Scholz, G. A., Hwang, Y. M., Rumfeldt, J. A., Lepock, J. R. and Meiering, E. M. Sonication of proteins causes formation of aggregates that resemble amyloid. Protein Sci 13(11): 3017-3027, 2004.
Stefani, M. and Dobson, C. M. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med 81(11): 678-699, 2003.
Su, Y. and Chang, P. T. Acidic pH promotes the formation of toxic fibrils from beta-amyloid peptide. Brain Res 893(1-2): 287-291, 2001.
Taboada, P., Barbosa, S., Castro, E. and Mosquera, V. Amyloid fibril formation and other aggregate species formed by human serum albumin association. J Phys Chem B Condens Matter Mater Surf Interfaces Biophys 110(42): 20733-20736, 2006.
Taboada, P., Barbosa, S., Castro, E. and Mosquera, V. Amyloid fibril formation and other aggregate species formed by human serum albumin association. J Phys Chem B 110(42): 20733-20736, 2006.
Taboga, O., Tami, C., Carrillo, E., Nunez, J. I., Rodriguez, A., Saiz, J. C., Blanco, E., Valero, M. L., Roig, X., Camarero, J. A., Andreu, D., Mateu, M. G., Giralt, E., Domingo, E., Sobrino, F. and Palma, E. L. A large-scale evaluation of peptide vaccines against foot-and-mouth disease: lack of solid protection in cattle and isolation of escape mutants. J Virol 71(4): 2606-2614, 1997.
Takada, Y., Ye, X. and Simon, S. The integrins. Genome Biol 8(5): 215, 2007.
Tamkun, J. W. and Hynes, R. O. Plasma fibronectin is synthesized and secreted by hepatocytes. J Biol Chem 258(7): 4641-4647, 1983.
Toker, A. Protein kinases as mediators of phosphoinositide 3-kinase signaling. Mol Pharmacol 57(4): 652-658, 2000.
Tooney, N. M., Mosesson, M. W., Amrani, D. L., Hainfeld, J. F. and Wall, J. S. Solution and surface effects on plasma fibronectin structure. J Cell Biol 97(6): 1686-1692, 1983.
Van Aelst, L. and D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev 11(18): 2295-2322, 1997.
van Lierop, M. J., Wagenaar, J. P., van Noort, J. M. and Hensen, E. J. Sequences derived from the highly antigenic VP1 region 140 to 160 of foot-and-mouth disease virus do not prime for a bovine T-cell response against intact virus. J Virol 69(7): 4511-4514, 1995.
Veerman, C., de Schiffart, G., Sagis, L. M. and van der Linden, E. Irreversible self-assembly of ovalbumin into fibrils and the resulting network rheology. Int J Biol Macromol 33(1-3): 121-127, 2003.
Wang, J. H., Liang, C. M., Peng, J. M., Shieh, J. J., Jong, M. H., Lin, Y. L., Sieber, M. and Liang, S. M. Induction of immunity in swine by purified recombinant VP1 of foot-and-mouth disease virus. Vaccine 21(25-26): 3721-3729, 2003.
Whitmore, L. and Wallace, B. A. DICHROWEB, an online server for protein secondary structure analyses from circular dichroism spectroscopic data. Nucleic Acids Res 32(Web Server issue): W668-673, 2004.
Wright, S., Malinin, N. L., Powell, K. A., Yednock, T., Rydel, R. E. and Griswold-Prenner, I. Alpha2beta1 and alphaVbeta1 integrin signaling pathways mediate amyloid-beta-induced neurotoxicity. Neurobiol Aging 28(2): 226-237, 2007.
Wu, C. J., O'Rourke, D. M., Feng, G. S., Johnson, G. R., Wang, Q. and Greene, M. I. The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors. Oncogene 20(42): 6018-6025, 2001.
Yan, S. D., Shi, Y., Zhu, A., Fu, J., Zhu, H., Zhu, Y., Gibson, L., Stern, E., Collison, K., Al-Mohanna, F., Ogawa, S., Roher, A., Clarke, S. G. and Stern, D. M. Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity. J Biol Chem 274(4): 2145-2156, 1999.
Yang, N. S., Wang, J. H., Lin, K. F., Wang, C. Y., Kim, S. A., Yang, Y. L., Jong, M. H., Kuo, T. Y., Lai, S. S., Cheng, R. H., Chan, M. T. and Liang, S. M. Comparative studies of the capsid precursor polypeptide P1 and the capsid protein VP1 cDNA vectors for DNA vaccination against foot-and-mouth disease virus. J Gene Med 7(6): 708-717, 2005.
Yi, M. and Ruoslahti, E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc Natl Acad Sci U S A 98(2): 620-624, 2001.
Yu, D. H., Qu, C. K., Henegariu, O., Lu, X. and Feng, G. S. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J Biol Chem 273(33): 21125-21131, 1998.
Zamotin, V., Gharibyan, A., Gibanova, N. V., Lavrikova, M. A., Dolgikh, D. A., Kirpichnikov, M. P., Kostanyan, I. A. and Morozova-Roche, L. A. Cytotoxicity of albebetin oligomers depends on cross-beta-sheet formation. FEBS Lett 580(10): 2451-2457, 2006.
Zhang, H., Ozaki, I., Mizuta, T., Matsuhashi, S., Yoshimura, T., Hisatomi, A., Tadano, J., Sakai, T. and Yamamoto, K. Beta 1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway. Cancer 95(4): 896-906, 2002.
Zhao, J. H. and Guan, J. L. Role of focal adhesion kinase in signaling by the extracellular matrix. Prog Mol Subcell Biol 25: 37-55, 2000.