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Showing Protein Prolyl endopeptidase FAP (HMDBP13490)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 3 metabolites
Identification
HMDB Protein ID HMDBP13490
Secondary Accession Numbers None
Name Prolyl endopeptidase FAP
Synonyms
  1. 170 kDa melanoma membrane-bound gelatinase
  2. Dipeptidyl peptidase FAP
  3. Fibroblast activation protein alpha
  4. Gelatine degradation protease FAP
  5. Integral membrane serine protease
  6. Post-proline cleaving enzyme
  7. Serine integral membrane protease
  8. Surface-expressed protease
  9. FAPalpha
  10. SIMP
  11. Seprase
Gene Name FAP
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Also has dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner.
Pathways Not Available
Reactions Not Available
GO Classification
Biological Process
melanocyte apoptotic process
melanocyte proliferation
negative regulation of cell proliferation involved in contact inhibition
negative regulation of extracellular matrix disassembly
negative regulation of extracellular matrix organization
positive regulation of cell cycle arrest
positive regulation of execution phase of apoptosis
regulation of collagen catabolic process
cell adhesion
endothelial cell migration
angiogenesis
regulation of fibrinolysis
proteolysis
mitotic cell cycle arrest
proteolysis involved in cellular protein catabolic process
Cellular Component
cell surface
peptidase complex
apical part of cell
basal part of cell
focal adhesion
cytoplasm
plasma membrane
ruffle membrane
lamellipodium membrane
lamellipodium
extracellular space
integral to membrane
Molecular Function
protease binding
dipeptidyl-peptidase activity
endopeptidase activity
peptidase activity
integrin binding
protein homodimerization activity
serine-type peptidase activity
serine-type endopeptidase activity
identical protein binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 760
Molecular Weight 87711.845
Theoretical pI 6.65
Pfam Domain Function
Signals Not Available
Transmembrane Regions
  • 5-25;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q12884
UniProtKB/Swiss-Prot Entry Name SEPR_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. [PubMed:15815621 ]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  3. Liu T, Qian WJ, Gritsenko MA, Camp DG 2nd, Monroe ME, Moore RJ, Smith RD: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005 Nov-Dec;4(6):2070-80. [PubMed:16335952 ]
  4. Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen WT: The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res. 2006 May 1;66(9):4652-61. [PubMed:16651416 ]
  5. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, Old LJ, Rettig WJ: Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5657-61. [PubMed:7911242 ]
  6. Goldstein LA, Ghersi G, Pineiro-Sanchez ML, Salamone M, Yeh Y, Flessate D, Chen WT: Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta. 1997 Jul 10;1361(1):11-9. [PubMed:9247085 ]
  7. Pineiro-Sanchez ML, Goldstein LA, Dodt J, Howard L, Yeh Y, Tran H, Argraves WS, Chen WT: Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem. 1997 Mar 21;272(12):7595-601. [PubMed:9065413 ]
  8. Goldstein LA, Chen WT: Identification of an alternatively spliced seprase mRNA that encodes a novel intracellular isoform. J Biol Chem. 2000 Jan 28;275(4):2554-9. [PubMed:10644713 ]
  9. Rettig WJ, Su SL, Fortunato SR, Scanlan MJ, Raj BK, Garin-Chesa P, Healey JH, Old LJ: Fibroblast activation protein: purification, epitope mapping and induction by growth factors. Int J Cancer. 1994 Aug 1;58(3):385-92. [PubMed:7519584 ]
  10. Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, Zhang Y, Kraus ML, Salakian S, Sridhar V, Wijnands R, Tennant MG: Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. J Biol Chem. 2005 May 20;280(20):19441-4. Epub 2005 Apr 4. [PubMed:15809306 ]
  11. Lee KN, Jackson KW, Christiansen VJ, Chung KH, McKee PA: A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion. Blood. 2004 May 15;103(10):3783-8. doi: 10.1182/blood-2003-12-4240. Epub 2004 Jan 29. [PubMed:14751930 ]
  12. Aoyama A, Chen WT: A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8296-300. doi: 10.1073/pnas.87.21.8296. [PubMed:2172980 ]
  13. Monsky WL, Lin CY, Aoyama A, Kelly T, Akiyama SK, Mueller SC, Chen WT: A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells. Cancer Res. 1994 Nov 1;54(21):5702-10. [PubMed:7923219 ]
  14. Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Muller E, Rettig WJ, Gorrell MD: Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology. 1999 Jun;29(6):1768-78. doi: 10.1002/hep.510290631. [PubMed:10347120 ]
  15. Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ: Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 1999 Dec 17;274(51):36505-12. doi: 10.1074/jbc.274.51.36505. [PubMed:10593948 ]
  16. Mueller SC, Ghersi G, Akiyama SK, Sang QX, Howard L, Pineiro-Sanchez M, Nakahara H, Yeh Y, Chen WT: A novel protease-docking function of integrin at invadopodia. J Biol Chem. 1999 Aug 27;274(35):24947-52. doi: 10.1074/jbc.274.35.24947. [PubMed:10455171 ]
  17. Artym VV, Kindzelskii AL, Chen WT, Petty HR: Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton. Carcinogenesis. 2002 Oct;23(10):1593-601. doi: 10.1093/carcin/23.10.1593. [PubMed:12376466 ]
  18. Wang XM, Yu DM, McCaughan GW, Gorrell MD: Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line. Hepatology. 2005 Oct;42(4):935-45. doi: 10.1002/hep.20853. [PubMed:16175601 ]
  19. Bauer S, Jendro MC, Wadle A, Kleber S, Stenner F, Dinser R, Reich A, Faccin E, Godde S, Dinges H, Muller-Ladner U, Renner C: Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther. 2006;8(6):R171. doi: 10.1186/ar2080. [PubMed:17105646 ]
  20. Edosada CY, Quan C, Tran T, Pham V, Wiesmann C, Fairbrother W, Wolf BB: Peptide substrate profiling defines fibroblast activation protein as an endopeptidase of strict Gly(2)-Pro(1)-cleaving specificity. FEBS Lett. 2006 Mar 6;580(6):1581-6. doi: 10.1016/j.febslet.2006.01.087. Epub 2006 Feb 3. [PubMed:16480718 ]
  21. Edosada CY, Quan C, Wiesmann C, Tran T, Sutherlin D, Reynolds M, Elliott JM, Raab H, Fairbrother W, Wolf BB: Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity. J Biol Chem. 2006 Mar 17;281(11):7437-44. doi: 10.1074/jbc.M511112200. Epub 2006 Jan 12. [PubMed:16410248 ]
  22. Meadows SA, Edosada CY, Mayeda M, Tran T, Quan C, Raab H, Wiesmann C, Wolf BB: Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization. Biochemistry. 2007 Apr 17;46(15):4598-605. doi: 10.1021/bi062227y. Epub 2007 Mar 24. [PubMed:17381073 ]
  23. Aggarwal S, Brennen WN, Kole TP, Schneider E, Topaloglu O, Yates M, Cotter RJ, Denmeade SR: Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites. Biochemistry. 2008 Jan 22;47(3):1076-86. doi: 10.1021/bi701921b. Epub 2007 Dec 21. [PubMed:18095711 ]
  24. O'Brien P, O'Connor BF: Seprase: an overview of an important matrix serine protease. Biochim Biophys Acta. 2008 Sep;1784(9):1130-45. doi: 10.1016/j.bbapap.2008.01.006. Epub 2008 Jan 26. [PubMed:18262497 ]
  25. Mentlein R, Hattermann K, Hemion C, Jungbluth AA, Held-Feindt J: Expression and role of the cell surface protease seprase/fibroblast activation protein-alpha (FAP-alpha) in astroglial tumors. Biol Chem. 2011 Mar;392(3):199-207. doi: 10.1515/BC.2010.119. [PubMed:20707604 ]
  26. Keane FM, Nadvi NA, Yao TW, Gorrell MD: Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-alpha. FEBS J. 2011 Apr;278(8):1316-32. doi: 10.1111/j.1742-4658.2011.08051.x. Epub 2011 Mar 9. [PubMed:21314817 ]
  27. Huang CH, Suen CS, Lin CT, Chien CH, Lee HY, Chung KM, Tsai TY, Jiaang WT, Hwang MJ, Chen X: Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate. J Biochem. 2011 Jun;149(6):685-92. doi: 10.1093/jb/mvr017. Epub 2011 Feb 1. [PubMed:21288888 ]
  28. Keane FM, Yao TW, Seelk S, Gall MG, Chowdhury S, Poplawski SE, Lai JH, Li Y, Wu W, Farrell P, Vieira de Ribeiro AJ, Osborne B, Yu DM, Seth D, Rahman K, Haber P, Topaloglu AK, Wang C, Thomson S, Hennessy A, Prins J, Twigg SM, McLennan SV, McCaughan GW, Bachovchin WW, Gorrell MD: Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio. 2013 Dec 8;4:43-54. doi: 10.1016/j.fob.2013.12.001. eCollection 2013. [PubMed:24371721 ]