The role of proteases in regulating Eph/ephrin signaling

Cell Adhesion and Migration

Volumn 8, Issue 4, 2014, Pages 294-307

  Atapattu, Lakmali ^a   Lackmann, Martin ^a   Janes, Peter W ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

ADAM; Eph receptor tyrosine kinase; Ephrin signaling; MMP; Protease; secretase

Indexed keywords

ADAM10 ENDOPEPTIDASE; CELL ADHESION MOLECULE; DISINTEGRIN; EPHRIN; EPHRIN RECEPTOR; GAMMA SECRETASE; MATRIX METALLOPROTEINASE; NEUROPSIN; PROTEINASE; SERINE PROTEINASE; LIGAND; PEPTIDE HYDROLASE; PROTEIN BINDING;

ENZYME ACTIVITY; HUMAN; INTRACELLULAR SIGNALING; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CELL ADHESION; CELL COMMUNICATION; CELL MOTION; METABOLISM; MOUSE;

ANIMALS; CELL ADHESION; CELL COMMUNICATION; CELL MOVEMENT; EPHRINS; HUMANS; LIGANDS; MICE; PEPTIDE HYDROLASES; PROTEIN BINDING; RECEPTORS, EPH FAMILY; SIGNAL TRANSDUCTION;

EID: 84918804823     PISSN: 19336918     EISSN: 19336926     Source Type: Journal    
DOI: 10.4161/19336918.2014.970026     Document Type: Review

References (146)

1. Serim S, Haedke U, Verhelst SHL. Activity-based probes for the study of proteases: recent advances and developments. Chem Med Chem 2012;7:1146-59; PMID:22431376; http://dx.doi.org/10.1002/cmdc. 201200057
2. Drag M, Salvesen GS. Emerging principles in protease-based drug discovery. Nat Rev Drug Discov 2010;9:690-701; PMID:20811381; http://dx.doi.org/10. 1038/nrd3053
3. Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Dis 2006;5:785-99; PMID:16955069; http://dx.doi.org/10.1038/nrd2092
4. Lopez-Otin C, Bond JS. Proteases: multifunctional enzymes in life and disease. J Biol Chem 2008;283:30433-7; PMID:18650443; http://dx.doi.org/10.1074/jbc. R800035200
5. Overall CM, Blobel CP. In search of partners: linking extracellular proteases to substrates. Nat Rev Mol Cell Biol 2007;8:245-57; PMID:17299501; http://dx.doi.org/10.1038/nrm2120
6. Turk B, Turk D, Turk V. Protease signalling: the cutting edge. EMBO J 2012;31:1630-43; PMID:22367392; http://dx.doi.org/10.1038/emboj. 2012.42
7. Adrain C, Freeman M. Regulation of receptor tyrosine kinase ligand processing. Cold Spring Harb Perspect Biol 2014;6:pii: a008995; PMID:24384567; http://dx.doi.org/10.1101/cshperspect.a008995
8. Nievergall E, Lackmann M, Janes PW. Eph-dependent cell-cell adhesion and segregation in development and cancer. Cell Mol Life Sci 2012;69:1813-42; PMID:22204021; http://dx.doi.org/10.1007/s00018-011-0900-6
9. Marston DJ, Dickinson S, Nobes CD. Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol 2003;5:879-88; PMID:12973357; http://dx.doi.org/10.1038/ncb1044
10. Klein T, Bischoff R. Active metalloproteases of the A Disintegrin and Metalloprotease (ADAM) family: biological function and structure. J Proteome Res 2011;10:17-33; PMID:20849079; http://dx.doi.org/10.1021/pr100556z
11. Wolfsberg TG, White JM. 207-ADAM metalloproteinases. In: Barrett AJ, Rawlings ND, Woessner JF, eds. Handbook of Proteolytic Enzymes. Second Edition. London: Academic Press, 2004:709-14
12. Weber S, Saftig P. Ectodomain shedding and ADAMs in development. Development (Cambridge, England) 2012;139:3693-709; PMID:22991436; http://dx. doi.org/10.1242/dev. 076398
13. Reiss K, Saftig P. The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol 2009;20:126-37; PMID:19049889; http://dx. doi.org/10.1016/j.semcdb.2008.11.002
14. Tousseyn T, Jorissen E, Reiss K, Hartmann D. (Make) stick and cut loose-disintegrin metalloproteases in development and disease. Birth Defects Res C Embryo Today 2006;78:24-46; PMID:16622847; http://dx.doi.org/10.1002/bdrc.20066
15. Kurohara K, Komatsu K, Kurisaki T, Masuda A, Irie N, Asano M, Sudo K, Nabeshima Y, Iwakura Y, Sehara-Fujisawa A. Essential roles of Meltrin beta (ADAM19) in heart development. Dev Biol 2004;267:14-28; PMID:14975714; http://dx.doi.org/10.1016/j.ydbio.2003.10.021
16. Murphy G. The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 2008;8:929-41; PMID:19005493; http://dx.doi.org/10.1038/nrc2459
17. Blobel CP. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 2005;6:32-43; PMID:15688065; http://dx.doi.org/10.1038/nrm1548
18. Loechel F, Overgaard MT, Oxvig C, Albrechtsen R, Wewer UM. Regulation of human ADAM 12 protease by the prodomain. Evidence for a functional cysteine switch. J Biol Chem 1999;274:13427-33; PMID:10224107; http://dx.doi.org/10.1074/jbc.274. 19.13427
19. Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F. Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J 2001;15:1837-9; PMID:11481247
20. Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 2003;17:7-30; PMID:12514095; http://dx.doi.org/10.1101/gad.1039703
21. Fahrenholz F, Gilbert S, Kojro E, Lammich S, Postina R. Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure. Ann N Y Acad Sci 2000;920:215-22; PMID:11193153; http://dx.doi.org/10.1111/j.1749-6632. 2000.tb06925.x
22. Howard L, Maciewicz RA, Blobel CP. Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28. Biochem J 2000;348 Pt 1:21-7; PMID:10794709; http://dx.doi.org/10.1042/0264-6021:3480021
23. Roghani M, Becherer JD, Moss ML, Atherton RE, Erdjument-Bromage H, Arribas J, Blackburn RK, Weskamp G, Tempst P, Blobel CP. Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity. J Biol Chem 1999;274:3531-40; PMID:9920899; http://dx.doi.org/10.1074/jbc.274.6.3531
24. Lum L, Reid MS, Blobel CP. Intracellular maturation of the mouse metalloprotease disintegrin MDC15. J Biol Chem 1998;273:26236-47; PMID:9748307; http://dx.doi.org/10.1074/jbc.273.40.26236
25. Laisney JAGC, Mueller TD, Schartl M, Meierjohann S. Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops. Oncogene 2013;32:2403-11; PMID:22751127; http://dx.doi.org/10.1038/onc.2012.267
26. Moss ML, Bomar M, Liu Q, Sage H, Dempsey P, Lenhart PM, Gillispie PA, Stoeck A, Wildeboer D, Bartsch JW, et al. The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events. J Biol Chem 2007;282:35712-21; PMID:17895248; http://dx.doi.org/10.1074/jbc. M703231200
27. Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM. Human ADAM 12 (meltrin alpha) is an active metalloprotease. J Biol Chem 1998;273:16993-7; PMID:9642263; http://dx.doi.org/10.1074/jbc.273.27.16993
28. Saftig P, Reiss K. The "A Disintegrin And Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential? Eur J Cell Biol 2011;90:527-35; PMID:21194787; http://dx.doi.org/10.1016/j.ejcb.2010.11.005
29. White JM. ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 2003;15:598-606; PMID:14519395; http://dx.doi.org/10.1016/j.ceb.2003.08.001
30. Caescu CI, Jeschke GR, Turk BE. Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem J 2009;424:79-88; PMID:19715556; http://dx.doi.org/10.1042/BJ20090549
31. Moss ML, Lambert MH. Shedding of membrane proteins by ADAM family proteases. Essays Biochem 2002;38:141-53; PMID:12463167
32. Smith KM, Gaultier A, Cousin H, Alfandari D, White JM, De Simone DW. The cysteine-rich domain regulates ADAM protease function in vivo. J Cell Biol 2002;159:893-902; PMID:12460986; http://dx.doi.org/10.1083/jcb.200206023
33. Alfandari D. ADAM13 Function in Development. In: Hooper N, Lendeckel U, eds. The ADAM Family of Proteases: Springer US, 2005:147-69
34. Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA. Functional analysis of the domain structure of tumor necrosis factor-a converting enzyme. J Biol Chem 2000;275:14608-14; PMID:10799547; http://dx. doi.org/10.1074/jbc.275.19.14608
35. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005;123:291-304; PMID:16239146; http://dx.doi.org/10.1016/j.cell.2005.08.014
36. Maskos K, Fernandez-Catalan C, Huber R, Bourenkov GP, Bartunik H, Ellestad GA, Reddy P, Wolfson MF, Rauch CT, Castner BJ, et al. Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme. Proc Natl Acad Sci U S A 1998;95:3408-12; PMID:9520379; http://dx.doi.org/10.1073/pnas.95.7.3408
37. Takeda S, Igarashi T, Mori H, Araki S. Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold. EMBO J 2006;25:2388-96; PMID:16688218; http://dx.doi.org/10.1038/sj.emboj.7601131
38. Kullander K, Klein R. Mechanisms and functions of eph and ephrin signalling. Nat Rev Mol Cell Biol 2002;3:475-86; PMID:12094214; http://dx.doi.org/10.1038/nrm856
39. Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000;289:1360-5; PMID:10958785; http://dx.doi.org/10.1126/science.289.5483.1360
40. Sahin U, Weskamp G, Kelly K, Zhou H-M, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 2004;164:769-79; PMID:14993236; http://dx.doi.org/10.1083/jcb.200307137
41. Luo X, Prior M, He W, Hu X, Tang X, Shen W, Yadav S, Kiryu-Seo S, Miller R, Trapp S, et al. Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination. J Biol Chem 2011;286:23967-74; PMID:21576249; http://dx.doi.org/10.1074/jbc. M111.251538
42. Pruessmeyer J, Ludwig A. The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol 2009;20:164-74; PMID:18951988; http://dx. doi.org/10.1016/j.semcdb.2008.09.005
43. Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Sedlacek R, Dietrich S, Muetze B, et al. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol 2004;172:6362-72; PMID:15128827; http://dx.doi.org/10.4049/jimmunol.172.10.6362
44. Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 2003;102:1186-95; PMID:12714508; http://dx.doi.org/10.1182/blood-2002-12-3775
45. Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, De Strooper B, Hartmann D, Saftig P. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation. Proc Natl Acad Sci U S A 2005;102:9182-7; PMID:15958533; http://dx.doi.org/10.1073/pnas.0500918102
46. Reiss K, Maretzky T, Ludwig A, Tousseyn T, De Strooper B, Hartmann D, Saftig P. ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and β-catenin nuclear signalling. EMBO J 2005;24:742-52.
47. Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Gast D, Joumaa S, Zentgraf H, Fogel M, Altevogt DP. ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles. FASEB J 2003;17:292-4; PMID:12475894
48. Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010;29:3020-32; PMID:20676056; http://dx.doi.org/10.1038/emboj.2010.167
49. Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D, De Strooper B, Grassi J, Lopez-Perez E, Checler F. The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. J Biol Chem 2001;276:37743-6; PMID:11477090; http://dx.doi.org/10.1074/jbc. M003965200
50. Ludwig A, Hundhausen C, Lambert MH, Broadway N, Andrews RC, Bickett DM, Leesnitzer MA, Becherer JD. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005;8:161-71; PMID:15777180; http://dx.doi.org/10.2174/1386207053258488
51. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-89; PMID:16921404; http://dx.doi.org/10.1038/nrm2009
52. D'Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands. Oncogene 2008;27:5148-67; http://dx.doi.org/10.1038/onc.2008.229
53. Zolkiewska A. ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci 2008;65:2056-68; PMID:18344021; http://dx. doi.org/10.1007/s00018-008-7586-4
54. Hartmann D, De Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lübke T, Lena Illert A, Von Figura K, et al. The disintegrinmetalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 2002;11:2615-24; PMID:12354787; http://dx.doi.org/10.1093/hmg/11.21.2615
55. Mancia F, Shapiro L. ADAM and Eph: how Ephrinsignaling cells become detached. Cell 2005;123:185-7; PMID:16239135; http://dx.doi.org/10.1016/j. cell.2005.10.004
56. Salaita K, Nair PM, Petit RS, Neve RM, Das D, Gray JW, Groves JT. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 2010;327:1380-5; PMID:20223987; http://dx. doi.org/10.1126/science.1181729
57. Atapattu L, Saha N, Llerena C, Vail ME, Scott AM, Nikolov DB, Lackmann M, Janes PW. Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function. J Cell Sci 2012;125:6084-93; PMID:23108669; http://dx.doi.org/10.1242/jcs.112631
58. Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, Grabenbauer M, Ting AY, Saftig P, Bastiaens PI, et al. Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS Biol 2009;7:e1000215; PMID:19823572; http://dx.doi.org/10.1371/journal. pbio.1000215
59. Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 2001;106:745-57; PMID:11572780; http://dx.doi.org/10.1016/S0092-8674 (01) 00496-2
60. Wang Y, Herrera AH, Li Y, Belani KK, Walcheck B. Regulation of mature ADAM17 by redox agents for L-selectin shedding. J Immunol 2009;182:2449-57; PMID:19201900; http://dx.doi.org/10.4049/jimmunol. 0802770
61. Willems SH, Tape CJ, Stanley PL, Taylor NA, Mills IG, Neal DE, McCafferty J, Murphy G, et al. Thiol isomerases negatively regulate the cellular shedding activity of ADAM17. Biochem J 2010;428:439-50; PMID:20345372; http://dx.doi.org/10.1042/BJ20100179
62. Dusterhoft S, Jung S, Hung CW, Tholey A, Sonnichsen FD, Grotzinger J, Lorenzen I. Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase. J Am Chem Soc 2013;135:5776-81; PMID:23521534; http://dx.doi.org/10.1021/ja400340u
63. Chiarugi P, Cirri P. Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem Sci 2003;28:509-14; PMID:13678963; http://dx.doi.org/10.1016/S0968-0004 (03) 00174-9
64. Chiarugi P, Buricchi F. Protein tyrosine phosphorylation and reversible oxidation: two cross-talking posttranslation modifications. Antioxid Redox Signal 2007;9:1-24; PMID:17115885; http://dx.doi.org/10.1089/ars.2007.9.1
65. Van Kempen LCL, De Visser KE, Coussens LM. Inflammation, proteases and cancer. Eur J Cancer 2006;42:728-34; PMID:16524717; http://dx.doi.org/10.1016/j.ejca.2006.01.004
66. Hartmann M, Herrlich A, Herrlich P. Who decides when to cleave an ectodomain? Trends Biochem Sci 2013;38:111-20; PMID:23298902; http://dx.doi.org/10.1016/j.tibs.2012.12.002
67. Ji YJ, Hwang YS, Mood K, Cho HJ, Lee HS, Winterbottom E, Cousin H, Daar IO. EphrinB2 affects apical constriction in Xenopus embryos and is regulated by ADAM10 and flotillin-1. Nat Commun 2014;5:3516; PMID:24662724
68. Gauthier LR, Robbins SM. Ephrin signaling: One raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them? Life Sci 2003;74:207-16; PMID:14607248; http://dx.doi.org/10.1016/j.lfs.2003.09.029
69. Marquardt T, Shirasaki R, Ghosh S, Andrews SE, Carter N, Hunter T, Pfaff SL. Coexpressed EphA receptors and Ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 2005;121:127-39; PMID:15820684; http://dx.doi.org/10.1016/j.cell.2005.01.020
70. Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, Ohmoto H, Node K, Yoshino K, Ishiguro H, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med 2002;8:35-40; PMID:11786904; http://dx.doi.org/10.1038/nm0102-35
71. Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 2004;279:51323-30; PMID:15381692; http://dx.doi.org/10.1074/jbc. M409565200
72. Kodama T, Ikeda E, Okada A, Ohtsuka T, Shimoda M, Shiomi T, Yoshida K, Nakada M, Ohuchi E, Okada Y. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am J Pathol 2004;165:1743-53; PMID:15509542; http://dx.doi.org/10.1016/S0002-9440 (10) 63429-3
73. Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy SL, Coulthard MG, Boyd A, Maru Y. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene 2014;33:2179-90; PMID:23686306; http://dx.doi.org/10.1038/onc.2013.180
74. Frohlich C, Nehammer C, Albrechtsen R, Kronqvist P, Kveiborg M, Sehara-Fujisawa A, Mercurio AM, Wewer UM. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression. Mol Cancer Res 2011;9:1449-61; PMID:21875931; http://dx.doi.org/10.1158/1541-7786. MCR-11-0100
75. Wei S, Xu G, Bridges LC, Williams P, White JM, De Simone DW. ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling. Dev Cell 2010;19:345-52; PMID:20708595; http://dx.doi.org/10.1016/j.devcel.2010.07.012
76. Gaultier A, Cousin H, Darribere T, Alfandari D. ADAM13 disintegrin and cysteine-rich domains bind to the second heparin-binding domain of fibronectin. J Biol Chem 2002;277:23336-44; PMID:11967265; http://dx.doi.org/10.1074/jbc. M201792200
77. Alfandari D, Cousin H, Gaultier A, Smith K, White JM, Darribere T, De Simone DW. Xenopus ADAM 13 is a metalloprotease required for cranial neural crest-cell migration. Curr Biol 2001;11:918-30; PMID: 11448768; http://dx.doi.org/10.1016/S0960-9822 (01) 00263-9
78. McCusker C, Cousin H, Neuner R, Alfandari D. Extracellular cleavage of cadherin-11 by ADAM metalloproteases is essential for Xenopus cranial neural crest cell migration. Mol Biol Cell 2009;20:78-89; PMID: 18946084; http://dx.doi.org/10.1091/mbc. E08-05-0535
79. Cousin H, Abbruzzese G, Kerdavid E, Gaultier A, Alfandari D. Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain8-a expression and cranial neural crest cell migration. Dev Cell 2011;20:256-63; PMID:21316592; http://dx. doi.org/10.1016/j.devcel.2010.12.009
80. Krull CE, Lansford R, Gale NW, Collazo A, Marcelle C, Yancopoulos GD, Fraser SE, Bronner-Fraser M. Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Cu Biol 1997;7:571-80; PMID:9259560; http://dx.doi.org/10.1016/S0960-9822 (06) 00256-9
81. Qi B, Newcomer RG, Sang Q-XA. ADAM19Adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. Curr Pharm Des 2009;15:2336-48; PMID:19601835; http://dx. doi.org/10.2174/138161209788682352
82. Yumoto N, Wakatsuki S, Kurisaki T, Hara Y, Osumi N, Frisen J, Sehara-Fujisawa A. Meltrin betaADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction. PloS One 2008;3:e3322; PMID:18830404; http://dx.doi.org/10.1371/journal.pone.0003322
83. Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol 2011;13:1100-7; PMID:21804545; http://dx.doi.org/10.1038/ncb2298
84. Brennaman LH, Zhang X, Guan H, Triplett JW, Brown A, Demyanenko GP, Manis PB, Landmesser L, Maness PF. Polysialylated NCAM and EphrinAEphA regulate synaptic development of GABAergic interneurons in prefrontal cortex. Cereb Cortex 2013;23:162-77; PMID:22275477; http://dx.doi.org/10.1093/cercor/bhr392
85. Batlle E, Henderson JT, Beghtel H, Van Den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, Van De Wetering M, Pawson T, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphBephrinB. Cell 2002;111:251-63; PMID:12408869; http://dx. doi.org/10.1016/S0092-8674 (02) 01015-2
86. Cortina C, Palomo-Ponce S, Iglesias M, Fernandez-Masip JL, Vivancos A, Whissell G, Huma M, Peiro N, Gallego L, Jonkheer S, et al. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet 2007;39:1376-83; PMID:17906625; http://dx.doi.org/10.1038/ng.2007.11
87. Chen Y, Fu AKY, Ip NY. Eph receptors at synapses: implications in neurodegenerative diseases. Cell Signal 2012;24:606-11; PMID:22120527; http://dx.doi.org/10.1016/j.cellsig.2011.11.016
88. Brennaman LH, Moss ML, Maness PF. EphrinAEphA-induced ectodomain shedding of neural cell adhesion molecule regulates growth cone repulsion through ADAM10 metalloprotease. J Neurochem 2014;128:267-79; PMID:24117969; http://dx.doi.org/10.1111/jnc.12468
89. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007;8:221-33; PMID:17318226; http://dx.doi.org/10.1038/nrm2125
90. Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4:617-29; PMID:15286728; http://dx.doi.org/10.1038/nri1418
91. Streuli C. Extracellular matrix remodelling and cellular differentiation. Curr Opin Cell Biol 1999;11:634-40; PMID:10508658; http://dx.doi.org/10.1016/S0955-0674 (99) 00026-5
92. Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, et al. An essential role for ectodomain shedding in mammalian development. Science 1998;282:1281-4; PMID:9812885; http://dx.doi.org/10.1126/science.282.5392.1281
93. Palmisano R, Itoh Y. Analysis of MMP-Dependent Cell Migration and Invasion. Meth Molec Bio 2010;622:379-92.
94. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141:52-67; PMID:20371345; http://dx. doi.org/10.1016/j.cell.2010.03.015
95. Beauchamp A, Lively MO, Mintz A, Gibo D, Wykosky J, Debinski W. EphrinA1 is released in three forms from cancer cells by matrix metalloproteases. Mol Cell Biol 2012;32:3253-64; PMID:22688511; http://dx.doi.org/10.1128/MCB.06791-11
96. Parri M, Taddei ML, Bianchini F, Calorini L, Chiarugi P. EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboidlike motility style. Cancer Res 2009;69:2072-81; PMID:19244130; http://dx.doi.org/10.1158/0008-5472. CAN-08-1845
97. Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-82; PMID:15492828
98. Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK. MetalloproteinasePresenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 2006;25:1242-52; PMID:16511561; http://dx.doi.org/10.1038/sj.emboj.7601031
99. Tanaka M, Sasaki K, Kamata R, Sakai R. The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells. J Cell Sci 2007;120:2179-89; PMID:17567680; http://dx.doi.org/10.1242/jcs.008607
100. Tanaka M, Kamata R, Yanagihara K, Sakai R. Suppression of gastric cancer dissemination by ephrin-B1-derived peptide. Cancer Sci 2010;101:87-93; PMID:19804421; http://dx.doi.org/10.1111/j.1349-7006.2009.01352.x
101. Lee HS, Bong YS, Moore KB, Soria K, Moody SA, Daar IO. Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway. Nat Cell Biol 2006;8:55-63; PMID:16362052; http://dx.doi.org/10.1038/ncb1344
102. Ogawa K, Wada H, Okada N, Harada I, Nakajima T, Pasquale EB, Tsuyama S. EphB2 and ephrin-B1 expressed in the adult kidney regulate the cytoarchitecture of medullary tubule cells through Rho family GTPases. J Cell Sci 2006;119:559-70; PMID:16443753; http://dx.doi.org/10.1242/jcs.02777
103. Lin KT, Sloniowski S, Ethell DW, Ethell IM. Ephrin-B2-induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion. J Biol Chem 2008;283:28969-79; PMID:18713744; http://dx.doi.org/10.1074/jbc. M804401200
104. Moeller ML, Shi Y, Reichardt LF, Ethell IM. EphB receptors regulate dendritic spine morphogenesis through the recruitmentphosphorylation of focal adhesion kinase and RhoA activation. J Biol Chem 2006;281:1587-98; PMID:16298995; http://dx.doi.org/10.1074/jbc. M511756200
105. Chukkapalli S, Amessou M, Dilly AK, Dekhil H, Zhao J, Liu Q, Bejna A, Thomas RD, Bandyopadhyay S, Bismar TA, et al. Role of the EphB2 receptor in autophagy, apoptosis and invasion in human breast cancer cells. Exp Cell Res 2014;320:233-46; PMID:24211352; http://dx.doi.org/10.1016/j.yexcr.2013.10.022
106. Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK. Ligand binding and calcium influx induce distinct ectodomaingamma-secretase-processing pathways of EphB2 receptor. J Biol Chem 2007;282:16155-63; PMID:17428795; http://dx.doi.org/10.1074/jbc. M611449200
107. Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiainen M, Gstaiger M, Gstaiger M, Lehti K. EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion. J Cell Biol 2013;201:467-84; PMID:23629968; http://dx.doi.org/10.1083/jcb.201205176
108. Suenaga N, Mori H, Itoh Y, Seiki M. CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. Oncogene 2005;24:859-68; PMID:15558018; http://dx.doi.org/10.1038/sj.onc.1208258
109. Yuan W, Chen Z, Chen Z, Wu S, Guo J, Ge J, Yang P, Huang J. Silencing of EphA2 inhibits invasion of human gastric cancer SGC-7901 cells in vitro and in vivo. Neoplasma 2012;59:105-13; PMID:22103904; http://dx.doi.org/10.4149/neo-2012-014
110. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness. Biochem Biophys Res Commun 2004;320:1096-102; PMID:15249202; http://dx.doi.org/10.1016/j.bbrc.2004.06.054
111. Noren NK, Foos G, Hauser CA, Pasquale EB. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol 2006;8:815-25; PMID:16862147; http://dx.doi.org/10.1038/ncb1438
112. Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH, Granger HJ. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 2002;277:43830-5; PMID:12235151; http://dx.doi.org/10.1074/jbc. M207221200
113. Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000;100:391-8; PMID:10693756; http://dx.doi.org/10.1016/S0092-8674 (00) 80675-3
114. Lichtenthaler SF, Haass C, Steiner H. Regulated intramembrane proteolysis - lessons from amyloid precursor protein processing. J Neurochem 2011;117:779-96; PMID:21413990; http://dx.doi.org/10.1111/j.1471-4159.2011.07248.x
115. Murphy G, Murthy A, Khokha R. Clipping, shedding and RIPping keep immunity on cue. Trends Immunol 2008;29:75-82; PMID:18182322; http://dx.doi.org/10.1016/j.it.2007.10.009
116. Prox J, Rittger A, Saftig P. Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin. Exp Brain Res 2012;217:331-41; PMID:22120156; http://dx.doi.org/10.1007/s00221-011-2952-0
117. Strooper BD, Annaert W. Presenilins and the intramembrane proteolysis of proteins: facts and fiction. Nat Cell Bio 2001;3:E221-5.
118. Morohashi Y, Tomita T. Protein trafficking and maturation regulate intramembrane proteolysis. Biochim Biophys Acta 2013;1828:2855-61; PMID:23770323; http://dx.doi.org/10.1016/j.bbamem.2013.06.001
119. Rawson RB. Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus. Essays Biochem 2002;38:155-68; PMID:12463168
120. Nakayama K, Nagase H, Koh C-S, Ohkawara T. γ-secretase-regulated signaling: notch, APP, and Alzheimer's disease. Curr Psychopharmacol 2012;1:155-66; http://dx. doi.org/10.2174/2211556011201020155
121. Ni C-Y, Murphy MP, Golde TE, Carpenter G. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179-81; PMID: 11679632; http://dx.doi.org/10.1126/science. 1065412
122. Wolfe MS. Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases. Biol Chem 2010;391:839-47; PMID:20482315; http://dx.doi.org/10.1515/bc.2010.086
123. Bergmans BA, De Strooper B. γ-secretases: from cell biology to therapeutic strategies. Lancet Neurol 2010;9:215-26; PMID:20129170; http://dx.doi.org/10.1016/S1474-4422 (09) 70332-1
124. Georgakopoulos A, Xu J, Xu C, Mauger G, Barthet G, Robakis NK. Presenilin1gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomainsCsk binding protein. FASEB J 2011;25:3594-604; PMID:21746865; http://dx.doi.org/10.1096/fj.11-187856
125. Playford MP, Schaller MD. The interplay between Src and integrins in normal and tumor biology. Oncogene 2004;23:7928-46; PMID:15489911; http://dx.doi.org/10.1038/sj.onc. 1208080
126. Kanou T, Oneyama C, Kawahara K, Okimura A, Ohta M, Ikeda N, Shintani Y, Okumura M, Okada M. The transmembrane adaptor CbpPAG1 controls the malignant potential of human non-small celllung cancers that have c-Src upregulation. Mol Cancer Res 2011;9:103-14; PMID:21156787; http://dx.doi.org/10.1158/1541-7786. MCR-10-0340
127. Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 1992;258:1903-10; PMID:1361685; http://dx.doi.org/10.1126/science. 1361685
128. Lu YM, Roder JC, Davidow J, Salter MW. Src activation in the tnduction of long-term potentiation in CA1 hippocampal neurons. Science 1998;279:1363-8; PMID:9478899; http://dx.doi.org/10.1126/science.279.5355.1363
129. Henderson JT, Georgiou J, Jia Z, Robertson J, Elowe S, Roder JC, Pawson T. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 2001;32:1041-56; PMID:11754836; http://dx.doi.org/10.1016/S0896-6273 (01) 00553-0
130. Ionides EL, Fang KS, Rivkah Isseroff R, Oster GF. Stochastic models for cell motion and taxis. J Math Biol 2004;48:23-37; PMID:14685770; http://dx.doi.org/10.1007/s00285-003-0220-z
131. Danysz W, Parsons CG. Alzheimer's disease, betaamyloid, glutamate, NMDA receptors and memantine-searching for the connections. Br J Pharmacol 2012;167:324-52; PMID:22646481; http://dx.doi.org/10.1111/j.1476-5381.2012.02057.x
132. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005;8:1051-8; PMID:16025111; http://dx.doi.org/10.1038/nn1503
133. Inoue E, Deguchi-Tawarada M, Togawa A, Matsui C, Arita K, Katahira-Tayama S, Sato T, Yamauchi E, Oda Y, Takai Y. Synaptic activity prompts gamma-secretasemediated cleavage of EphA4 and dendritic spine formation. J Cell Biol 2009;185:551-64; PMID:19414612; http://dx.doi.org/10.1083/jcb.200809151
134. Matsui C, Inoue E, Kakita A, Arita K, Deguchi-Tawarada M, Togawa A, Yamada A, Takai Y, Takahashi H. Involvement of the gamma-secretase-mediated EphA4 signaling pathway in synaptic pathogenesis of Alzheimer's disease. Brain Pathol 2012;22:776-87; PMID:22404518; http://dx.doi.org/10.1111/j.1750-3639.2012.00587.x
135. Hedstrom L. Serine protease mechanism and specificity. Chem Rev 2002;102:4501-24; PMID:12475199; http://dx.doi.org/10.1021/cr000033x
136. Polgar L. The catalytic triad of serine peptidases. Cellular and molecular life sciences: CMLS 2005;62:2161-72; PMID:16003488; http://dx.doi.org/10.1007/s00018-005-5160-x
137. Netzel-Arnett S, Hooper JD, Szabo R, Madison EL, Quigley JP, Bugge TH, Antalis TM. Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev 2003;22:237-58; PMID:12784999; http://dx.doi.org/10.1023/A:1023003616848
138. Santos J, Graindorge A, Soldati-Favre D. New insights into parasite rhomboid proteases. Mol Biochem Parasitol 2012;182:27-36; PMID:22173057; http://dx.doi.org/10.1016/j.molbiopara.2011.11.010
139. Lemberg MK, Menendez J, Misik A, Garcia M, Koth CM, Freeman M. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J 2005;24:464-72.
140. Lee JR, Urban S, Garvey CF, Freeman M. Regulated intracellular ligand transport and proteolysis control EGF signal activation in drosophila. Cell 2001;107:161-71; PMID:11672524; http://dx.doi.org/10.1016/S0092-8674 (01) 00526-8
141. Adrain C, Strisovsky K, Zettl M, Hu L, Lemberg MK, Freeman M. Mammalian EGF receptor activation by the rhomboid protease RHBDL2. EMBO Rep 2011;12:421-7; PMID:21494248; http://dx.doi.org/10.1038/embor.2011.50
142. Pascall JC, Brown KD. Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2. Biochem Biophys Res Commun 2004;317:244-52; PMID:15047175; http://dx.doi.org/10.1016/j.bbrc.2004.03.039
143. Chen ZL, Yoshida S, Kato K, Momota Y, Suzuki J, Tanaka T, Ito J, Nishino H, Aimoto S, Kiyama H, et al. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J Neurosci 1995;15:5088-97; PMID:7623137
144. Kishi T, Kato M, Shimizu T, Kato K, Matsumoto K, Yoshida S, Shiosaka S, Hakoshima T. Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. J Biol Chem 1999;274:4220-4; PMID:9933620; http://dx.doi.org/10.1074/jbc.274.7.4220
145. Shiosaka S, Ishikawa Y. Neuropsin-A possible modulator of synaptic plasticity. J Chem Neuroanat 2011;42:24-9; PMID:21679765; http://dx.doi.org/10.1016/j.jchemneu.2011.05.014
146. Attwood BK, Bourgognon J-M, Patel S, Mucha M, Schiavon E, Skrzypiec AE, Young KW, Shiosaka S, Korostynski M, Piechota M, et al. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 2011;473:372-5; PMID:21508957; http://dx.doi.org/10.1038/nature09938