Regulation of receptor for advanced glycation end products (rage) ectodomain shedding and its role in cell function

Journal of Biological Chemistry

Volumn 291, Issue 23, 2016, Pages 12057-12073

  Braley, Alex ^a   Kwak, Taekyoung ^a   Jules, Joel ^a   Harja, Evis ^a   Landgraf, Ralf ^a   Hudson, Barry I ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL MEMBRANES; CELLS; CYTOLOGY; GLYCOSYLATION; LIGANDS; PROTEINS; PROTEOLYSIS; SIGNALING;

ACTIN CYTOSKELETON; ADVANCED GLYCATION END PRODUCTS; CHEMICAL ACTIVATORS; ECTODOMAIN SHEDDING; ECTOPIC EXPRESSIONS; PHORBOL 12 MYRISTATE 13 ACETATES; THERAPEUTIC TARGETS; TRANSMEMBRANE RECEPTORS;

CELL SIGNALING;

4 AMINOPHENYLMERCURIC ACETATE; ADAM10 ENDOPEPTIDASE; ADVANCED GLYCATION END PRODUCT RECEPTOR; ADVANCED GLYCATION END PRODUCT RECEPTOR AFFECTING AGENT; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IONOMYCIN; METALLOPROTEINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; PHORBOL 13 ACETATE 12 MYRISTATE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN VARIANT; SECRETASE; ISOPROTEIN; METALLOPROTEINASE;

ACTIN FILAMENT; ANIMAL CELL; ARTICLE; CELL ADHESION; CELL FUNCTION; CELL SPREADING; CONTROLLED STUDY; ECTODOMAIN; ECTODOMAIN SHEDDING; ECTOPIC EXPRESSION; ENZYME ACTIVATION; ENZYME ACTIVITY; HUMAN VERSUS ANIMAL COMPARISON; INTRACELLULAR SIGNALING; MIGRATION INHIBITION; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROCESSING; RAT; REGULATORY MECHANISM; SERUM; AMINO ACID SEQUENCE; ANIMAL; BINDING SITE; CELL MOTION; DRUG EFFECTS; GENETICS; HEK293 CELL LINE; HUMAN; METABOLISM; MOUSE; MUTATION; PHYSIOLOGY; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; TUMOR CELL LINE; WESTERN BLOTTING;

ADAM10 PROTEIN; ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTOR; AMINO ACID SEQUENCE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BINDING SITES; BLOTTING, WESTERN; CELL LINE, TUMOR; CELL MOVEMENT; CELL PHYSIOLOGICAL PHENOMENA; HEK293 CELLS; HUMANS; IONOMYCIN; METALLOPROTEASES; MICE; MUTATION; PROTEIN ISOFORMS; PROTEOLYSIS; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION; TETRADECANOYLPHORBOL ACETATE;

EID: 84974603084     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.702399     Document Type: Article

References (72)

1. Kalea, A. Z., Schmidt, A. M., and Hudson, B. I. (2009) RAGE: a novel biological and genetic marker for vascular disease. Clin. Sci. 116, 621-637
2. Taguchi, A., Blood, D. C., del Toro, G., Canet, A., Lee, D. C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M. A., Kislinger, T., Ingram, M., Lu, A., Tanaka, H., et al. (2000) Blockage of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354-360
3. Hudson, B. I., Kalea, A. Z., Del Mar Arriero, M., Harja, E., Boulanger, E., D'Agati, V., and Schmidt, A. M. (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J. Biol. Chem. 283, 34457-34468
4. Kalea, A. Z., See, F., Harja, E., Arriero, M., Schmidt, A. M., and Hudson, B. I. (2010) Alternatively spliced RAGEv1 inhibits tumorigenesis through suppression of JNK signaling. Cancer Res. 70, 5628-5638
5. Logsdon, C. D., Fuentes, M. K., Huang, E. H., and Arumugam, T. (2007) RAGE and RAGE ligands in cancer. Curr. Mol. Med. 7, 777-789
6. Park, L., Raman, K. G., Lee, K. J., Lu, Y., Ferran, L. J., Jr., Chow, W. S., Stern, D., and Schmidt, A. M. (1998) Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat. Med. 4, 1025-1031
7. Hudson, B. I., Carter, A. M., Harja, E., Kalea, A. Z., Arriero, M., Yang, H., Grant, P. J., and Schmidt, A. M. (2008) Identification, classification, and expression of RAGE gene splice variants. FASEB J. 22, 1572-1580
8. Galichet, A., Weibel, M., and Heizmann, C. W. (2008) Calcium-regulated intramembrane proteolysis of the RAGE receptor. Biochem. Biophys. Res. Commun. 370, 1-5
9. Raucci, A., Cugusi, S., Antonelli, A., Barabino, S. M., Monti, L., Bierhaus, A., Reiss, K., Saftig, P., and Bianchi, M. E. (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J. 22, 3716-3727
10. Zhang, L., Bukulin, M., Kojro, E., Roth, A., Metz, V. V., Fahrenholz, F., Nawroth, P. P., Bierhaus, A., and Postina, R. (2008) Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J. Biol. Chem. 283, 35507-35516
11. Garton, K. J., Gough, P. J., and Raines, E. W. (2006) Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J. Leukoc. Biol. 79, 1105-1116
12. Hayashida, K., Bartlett, A. H., Chen, Y., and Park, P. W. (2010) Molecular and cellular mechanisms of ectodomain shedding. Anat. Rec. 293, 925-937
13. Jia, H. P., Look, D. C., Tan, P., Shi, L., Hickey, M., Gakhar, L., Chappell, M. C., Wohlford-Lenane, C., and McCray, P. B., Jr. (2009) Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L84-L96
14. Hudson, B. I., Moon, Y. P., Kalea, A. Z., Khatri, M., Marquez, C., Schmidt, A. M., Paik, M. C., Yoshita, M., Sacco, R. L., DeCarli, C., Wright, C. B., and Elkind, M. S. (2011) Association of serum soluble receptor for advanced glycation end-products with subclinical cerebrovascular disease: the Northern Manhattan Study (NOMAS). Atherosclerosis 216, 192-198
15. Falcone, C., Emanuele, E., D'Angelo, A., Buzzi, M. P., Belvito, C., Cuccia, M., and Geroldi, D. (2005) Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arterioscler. Thromb. Vasc. Biol. 25, 1032-1037
16. Thomas, M. C., Söderlund, J., Lehto, M., Mäkinen, V. P., Moran, J. L., Cooper, M. E., Forsblom, C., Groop, P. H., and FinnDiane Study Group (2011) Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes. Diabetologia 54, 2669-2677
17. Montaner, J., Perea-Gainza, M., Delgado, P., Ribó, M., Chacón, P., Rosell, A., Quintana, M., Palacios, M. E., Molina, C. A., and Alvarez-Sabín, J. (2008) Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 39, 2280-2287
18. Yokota, C., Minematsu, K., Tomii, Y., Naganuma, M., Ito, A., Nagasawa, H., and Yamaguchi, T. (2009) Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients. J. Neurol. Sci. 287, 41-44
19. Park, H. Y., Yun, K. H., and Park, D. S. (2009) Levels of soluble receptor for advanced glycation end products in acute ischemic stroke without a source of cardioembolism. J. Clin. Neurol. 5, 126-132
20. Kalea, A. Z., Reiniger, N., Yang, H., Arriero, M., Schmidt, A. M., and Hudson, B. I. (2009) Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J. 23, 1766-1774
21. Sakaguchi, M., Murata, H., Yamamoto, K., Ono, T., Sakaguchi, Y., Motoyama, A., Hibino, T., Kataoka, K., and Huh, N. H. (2011) TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 6, e23132
22. Codony-Servat, J., Albanell, J., Lopez-Talavera, J. C., Arribas, J., and Baselga, J. (1999) Cleavage of the HER2 ectodomain is a pervanadateactivable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. Cancer Res. 59, 1196-1201
23. Jules, J., Maiguel, D., and Hudson, B. I. (2013) Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS One 8, e78267
24. Grobben, B., De Deyn, P. P., and Slegers, H. (2002) Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res. 310, 257-270
25. Naik, M. U., Stalker, T. J., Brass, L. F., and Naik, U. P. (2012) JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets. Blood 119, 3352-3360
26. Collec, E., El Nemer, W., Gauthier, E., Gane, P., Lecomte, M. C., Dhermy, D., Cartron, J. P., Colin, Y., Le van Kim, C., and Rahuel, C. (2007) Ubc9 interacts with Lu/BCAM adhesion glycoproteins and regulates their stability at the membrane of polarized MDCK cells. Biochem. J. 402, 311-319
27. Vega, F. M., Colomba, A., Reymond, N., Thomas, M., and Ridley, A. J. (2012) RhoB regulates cell migration through altered focal adhesion dynamics. Open Biol. 2, 120076
28. Hanford, L. E., Enghild, J. J., Valnickova, Z., Petersen, S. V., Schaefer, L. M., Schaefer, T. M., Reinhart, T. A., and Oury, T. D. (2004) Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J. Biol. Chem. 279, 50019-50024
29. Hirata, M., Umata, T., Takahashi, T., Ohnuma, M., Miura, Y., Iwamoto, R., and Mekada, E. (2001) Identification of serum factor inducing ectodomain shedding of proHB-EGF and studies of noncleavable mutants of proHB-EGF. Biochem. Biophys. Res. Commun. 283, 915-922
30. Killock, D. J., and Ivetí, A. (2010) The cytoplasmic domains of TNFαconverting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem. J. 428, 293-304
31. Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., Love, R., Perry, S., Paquette, N., Deane, R. J., Thiyagarajan, M., Zarcone, T., Fritz, G., Friedman, A. E., Miller, B. L., and Zlokovic, B. V. (2012) A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Investig. 122, 1377-1392
32. Li, W., Xie, L., Chen, Z., Zhu, Y., Sun, Y., Miao, Y., Xu, Z., and Han, X. (2010) Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 101, 1226-1233
33. Suganuma, M., Fujiki, H., Furuya-Suguri, H., Yoshizawa, S., Yasumoto, S., Kato, Y., Fusetani, N., and Sugimura, T. (1990) Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin. Cancer Res. 50, 3521-3525
34. Zhang, Z., Humphreys, B. D., and Bonventre, J. V. (2007) Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region. J. Am. Soc. Nephrol. 18, 2704-2714
35. Fitzgerald, M. L., Wang, Z., Park, P. W., Murphy, G., and Bernfield, M. (2000) Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J. Cell Biol. 148, 811-824
36. Sessa, L., Gatti, E., Zeni, F., Antonelli, A., Catucci, A., Koch, M., Pompilio, G., Fritz, G., Raucci, A., and Bianchi, M. E. (2014) The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PLoS One 9, e86903
37. Brakebusch, C., Varfolomeev, E. E., Batkin, M., and Wallach, D. (1994) Structural requirements for inducible shedding of the p55 tumor necrosis factor receptor. J. Biol. Chem. 269, 32488-32496
38. Müllberg, J., Oberthür, W., Lottspeich, F., Mehl, E., Dittrich, E., Graeve, L., Heinrich, P. C., and Rose-John, S. (1994) The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J. Immunol. 152, 4958-4968
39. Tang, P., Hung, M.-C., and Klostergaard, J. (1996) Length of the linking domain of human pro-tumor necrosis factor determines the cleavage processing. Biochemistry 35, 8226-8233
40. Chen, A., Engel, P., and Tedder, T. F. (1995) Structural requirements regulate endoproteolytic release of the L-selectin (CD62L) adhesion receptor from the cell surface of leukocytes. J. Exp. Med. 182, 519-530
41. Demling, N., Ehrhardt, C., Kasper, M., Laue, M., Knels, L., and Rieber, E. P. (2006) Promotion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tissue Res. 323, 475-488
42. Milutinovic, P. S., Englert, J. M., Crum, L. T., Mason, N. S., Ramsgaard, L., Enghild, J. J., Sparvero, L. J., Lotze, M. T., and Oury, T. D. (2014) Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products. PLoS One 9, e88259
43. Yamagishi, S., Adachi, H., Nakamura, K., Matsui, T., Jinnouchi, Y., Takenaka, K., Takeuchi, M., Enomoto, M., Furuki, K., Hino, A., Shigeto, Y., and Imaizumi, T. (2006) Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism 55, 1227-1231
44. Jäckel, A., Deichmann, M., Waldmann, V., Bock, M., and Näher, H. (1999) S-100β protein in serum, a tumor marker in malignant melanoma-current state of knowledge and clinical experience. Hautarzt 50, 250-256
45. Pietzsch, J., and Hoppmann, S. (2009) Human S100A12: a novel key player in inflammation? Amino Acids 36, 381-389
46. Arumugam, T., Ramachandran, V., Gomez, S. B., Schmidt, A. M., and Logsdon, C. D. (2012) S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clin. Cancer Res. 18, 4356-4364
47. Kang, R., Loux, T., Tang, D., Schapiro, N. E., Vernon, P., Livesey, K. M., Krasinskas, A., Lotze, M. T., and Zeh, H. J., 3rd (2012) The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc. Natl. Acad. Sci. U.S.A. 109, 7031-7036
48. Kang, R., Tang, D., Schapiro, N. E., Livesey, K. M., Farkas, A., Loughran, P., Bierhaus, A., Lotze, M. T., and Zeh, H. J. (2010) The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 17, 666- 676
49. Xiong, F., Leonov, S., Howard, A. C., Xiong, S., Zhang, B., Mei, L., McNeil, P., Simon, S., and Xiong, W. C. (2011) Receptor for advanced glycation end products (RAGE) prevents endothelial cell membrane resealing and regulates F-actin remodeling in a beta-catenin-dependent manner. J. Biol. Chem. 286, 35061-35070
50. Zhou, Z., Immel, D., Xi, C. X., Bierhaus, A., Feng, X., Mei, L., Nawroth, P., Stern, D. M., and Xiong, W. C. (2006) Regulation of osteoclast function and bone mass by RAGE. J. Exp. Med. 203, 1067-1080
51. Zen, K., Chen, C. X., Chen, Y. T., Wilton, R., and Liu, Y. (2007) Receptor for advanced glycation endproducts mediates neutrophil migration across intestinal epithelium. J. Immunol. 178, 2483-2490
52. Kislinger, T., Fu, C., Huber, B., Qu, W., Taguchi, A., Du Yan, S., Hofmann, M., Yan, S. F., Pischetsrieder, M., Stern, D., and Schmidt, A. M. (1999) Nϵ -(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J. Biol. Chem. 274, 31740-31749
53. Huang, J. S., Guh, J. Y., Chen, H. C., Hung, W. C., Lai, Y. H., and Chuang, L. Y. (2001) Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J. Cell. Biochem. 81, 102-113
54. Yeh, C. H., Sturgis, L., Haidacher, J., Zhang, X. N., Sherwood, S. J., Bjercke, R. J., Juhasz, O., Crow, M. T., Tilton, R. G., and Denner, L. (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGEmediated nuclear factor-κB transcriptional activation and cytokine secretion. Diabetes 50, 1495-1504
55. Lander, H. M., Tauras, J. M., Ogiste, J. S., Hori, O., Moss, R. A., and Schmidt, A. M. (1997) Activation of the receptor for advanced glycation end products triggers a p21ras -dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J. Biol. Chem. 272, 17810-17814
56. Huttunen, H. J., Fages, C., and Rauvala, H. (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J. Biol. Chem. 274, 19919-19924
57. Ichikawa, M., Williams, R., Wang, L., Vogl, T., and Srikrishna, G. (2011) S100A8/A9 activate key genes and pathways in colon tumor progression. Mol. Cancer Res. 9, 133-148
58. Björk, P., Källberg, E., Wellmar, U., Riva, M., Olsson, A., He, Z., Törngren, M., Liberg, D., Ivars, F., and Leanderson, T. (2013) Common interactions between S100A4 and S100A9 defined by a novel chemical probe. PLoS One 8, e63012
59. Leclerc, E., Fritz, G., Weibel, M., Heizmann, C. W., and Galichet, A. (2007) S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J. Biol. Chem. 282, 31317-31331
60. Lam, J. K., Wang, Y., Shiu, S. W., Wong, Y., Betteridge, D. J., and Tan, K. C. (2013) Effect of insulin on the soluble receptor for advanced glycation end products (RAGE). Diabet. Med. 30, 702-709
61. Waterhouse, A. M., Procter, J. B., Martin, D. M., Clamp, M., and Barton, G. J. (2009) Jalview Version 2-a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189-1191
62. Nagano, O., Murakami, D., Hartmann, D., De Strooper, B., Saftig, P., Iwatsubo, T., Nakajima, M., Shinohara, M., and Saya, H. (2004) Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation. J. Cell Biol. 165, 893-902
63. Kveiborg, M., Instrell, R., Rowlands, C., Howell, M., and Parker, P. J. (2011) PKCα and PKCδ regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways. PLoS One 6, e17168
64. Thompson, J. D., Gibson, T. J., and Higgins, D. G. (2002) Multiple sequence alignment using ClustalW and ClustalX. Curr. Protoc. Bioinformatics Chapter 2, Unit 2.3
65. Tucher, J., Linke, D., Koudelka, T., Cassidy, L., Tredup, C., Wichert, R., Pietrzik, C., Becker-Pauly, C., and Tholey, A. (2014) LC-MS based cleavage site profiling of the proteases ADAM10 and ADAM17 using proteome-derived peptide libraries. J. Proteome Res. 13, 2205-2214
66. Caescu, C. I., Jeschke, G. R., and Turk, B. E. (2009) Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem. J. 424, 79-88
67. Rawlings, N. D., Barrett, A. J., and Finn, R. (2016) Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 44, D343-D350
68. Veikkolainen, V., Vaparanta, K., Halkilahti, K., Iljin, K., Sundvall, M., and Elenius, K. (2011) Function of ERBB4 is determined by alternative splicing. Cell Cycle 10, 2647-2657
69. Wei,W. Lampe,L. Park,S. Vangara,B. S. Waldo,G. S. Cabantous,S. Subaran,S. S. Yang,D. Lakatta,E. G. Lin,L.2012Disulfide bonds within the C2 domain of RAGE play key roles in its dimerization and biogenesisPLoS One7e50736
70. Ma, W., Lee, S. E., Guo, J., Qu, W., Hudson, B. I., Schmidt, A. M., and Barile, G. R. (2007) RAGE ligand upregulation of VEGF secretion in ARPE-19 cells. Invest. Ophthalmol. Vis. Sci. 48, 1355-1361
71. Ma, W., Rai, V., Hudson, B. I., Song, F., Schmidt, A. M., and Barile, G. R. (2012) RAGE binds C1q and enhances C1q-mediated phagocytosis. Cell. Immunol. 274, 72-82
72. Bairoch, A., Apweiler, R., Wu, C. H., Barker, W. C., Boeckmann, B., Ferro, S., Gasteiger, E., Huang, H., Lopez, R., Magrane, M., Martin, M. J., Natale, D. A., O'Donovan, C., Redaschi, N., and Yeh, L. S. (2005) The Universal Protein Resource (UniProt). Nucleic Acids Res. 33, D154-D159