Prolyl endopeptidase FAP

Details

Name
Prolyl endopeptidase FAP
Synonyms
  • 170 kDa melanoma membrane-bound gelatinase
  • 3.4.21.26
  • Dipeptidyl peptidase FAP
  • FAPalpha
  • Fibroblast activation protein alpha
  • Gelatine degradation protease FAP
  • Integral membrane serine protease
  • Post-proline cleaving enzyme
  • Seprase
  • Serine integral membrane protease
  • SIMP
  • Surface-expressed protease
Gene Name
FAP
Organism
Humans
Amino acid sequence
>lcl|BSEQ0037242|Prolyl endopeptidase FAP
MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPN
WISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSK
LWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPP
FQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYG
DEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVT
DERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYD
AISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPG
RRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGR
TDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQV
YGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQ
ITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVY
TERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNA
QVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD
Number of residues
760
Molecular Weight
87711.845
Theoretical pI
6.63
GO Classification
Functions
dipeptidyl-peptidase activity / endopeptidase activity / integrin binding / metalloendopeptidase activity / peptidase activity / protease binding / protein dimerization activity / protein homodimerization activity / serine-type endopeptidase activity / serine-type peptidase activity
Processes
angiogenesis / cell adhesion / endothelial cell migration / melanocyte apoptotic process / melanocyte proliferation / mitotic cell cycle arrest / 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 / proteolysis / proteolysis involved in cellular protein catabolic process / regulation of collagen catabolic process / regulation of fibrinolysis
Components
apical part of cell / basal part of cell / cell surface / cytoplasm / extracellular space / focal adhesion / integral component of membrane / invadopodium membrane / lamellipodium / lamellipodium membrane / plasma membrane / ruffle membrane
General Function
Serine-type peptidase activity
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, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Have also 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.
Pfam Domain Function
Transmembrane Regions
5-25
Cellular Location
Cell surface
Gene sequence
>lcl|BSEQ0021361|Prolyl endopeptidase FAP (FAP)
ATGAAGACTTGGGTAAAAATCGTATTTGGAGTTGCCACCTCTGCTGTGCTTGCCTTATTG
GTGATGTGCATTGTCTTACGCCCTTCAAGAGTTCATAACTCTGAAGAAAATACAATGAGA
GCACTCACACTGAAGGATATTTTAAATGGAACATTTTCTTATAAAACATTTTTTCCAAAC
TGGATTTCAGGACAAGAATATCTTCATCAATCTGCAGATAACAATATAGTACTTTATAAT
ATTGAAACAGGACAATCATATACCATTTTGAGTAATAGAACCATGCTTTGGAGATACTCT
TACACAGCAACATATTACATCTATGACCTTAGCAATGGAGAATTTGTAAGAGGAAATGAG
CTTCCTCGTCCAATTCAGTATTTATGCTGGTCGCCTGTTGGGAGTAAATTAGCATATGTC
TATCAAAACAATATCTATTTGAAACAAAGACCAGGAGATCCACCTTTTCAAATAACATTT
AATGGAAGAGAAAATAAAATATTTAATGGAATCCCAGACTGGGTTTATGAAGAGGAAATG
CTTGCTACAAAATATGCTCTCTGGTGGTCTCCTAATGGAAAATTTTTGGCATATGCGGAA
TTTAATGATACGGATATACCAGTTATTGCCTATTCCTATTATGGCGATGAACAATATCCT
AGAACAATAAATATTCCATACCCAAAGGCTGGAGCTAAGAATCCCGTTGTTCGGATATTT
ATTATCGATACCACTTACCCTGCGTATGTAGGTCCCCAGGAAGTGCCTGTTCCAGCAATG
ATAGCCTCAAGTGATTATTATTTCAGTTGGCTCACGTGGGTTACTGATGAACGAGTATGT
TTGCAGTGGCTAAAAAGAGTCCAGAATGTTTCGGTCCTGTCTATATGTGACTTCAGGGAA
GACTGGCAGACATGGGATTGTCCAAAGACCCAGGAGCATATAGAAGAAAGCAGAACTGGA
TGGGCTGGTGGATTCTTTGTTTCAACACCAGTTTTCAGCTATGATGCCATTTCGTACTAC
AAAATATTTAGTGACAAGGATGGCTACAAACATATTCACTATATCAAAGACACTGTGGAA
AATGCTATTCAAATTACAAGTGGCAAGTGGGAGGCCATAAATATATTCAGAGTAACACAG
GATTCACTGTTTTATTCTAGCAATGAATTTGAAGAATACCCTGGAAGAAGAAACATCTAC
AGAATTAGCATTGGAAGCTATCCTCCAAGCAAGAAGTGTGTTACTTGCCATCTAAGGAAA
GAAAGGTGCCAATATTACACAGCAAGTTTCAGCGACTACGCCAAGTACTATGCACTTGTC
TGCTACGGCCCAGGCATCCCCATTTCCACCCTTCATGATGGACGCACTGATCAAGAAATT
AAAATCCTGGAAGAAAACAAGGAATTGGAAAATGCTTTGAAAAATATCCAGCTGCCTAAA
GAGGAAATTAAGAAACTTGAAGTAGATGAAATTACTTTATGGTACAAGATGATTCTTCCT
CCTCAATTTGACAGATCAAAGAAGTATCCCTTGCTAATTCAAGTGTATGGTGGTCCCTGC
AGTCAGAGTGTAAGGTCTGTATTTGCTGTTAATTGGATATCTTATCTTGCAAGTAAGGAA
GGGATGGTCATTGCCTTGGTGGATGGTCGAGGAACAGCTTTCCAAGGTGACAAACTCCTC
TATGCAGTGTATCGAAAGCTGGGTGTTTATGAAGTTGAAGACCAGATTACAGCTGTCAGA
AAATTCATAGAAATGGGTTTCATTGATGAAAAAAGAATAGCCATATGGGGCTGGTCCTAT
GGAGGATACGTTTCATCACTGGCCCTTGCATCTGGAACTGGTCTTTTCAAATGTGGTATA
GCAGTGGCTCCAGTCTCCAGCTGGGAATATTACGCGTCTGTCTACACAGAGAGATTCATG
GGTCTCCCAACAAAGGATGATAATCTTGAGCACTATAAGAATTCAACTGTGATGGCAAGA
GCAGAATATTTCAGAAATGTAGACTATCTTCTCATCCACGGAACAGCAGATGATAATGTG
CACTTTCAAAACTCAGCACAGATTGCTAAAGCTCTGGTTAATGCACAAGTGGATTTCCAG
GCAATGTGGTACTCTGACCAGAACCACGGCTTATCCGGCCTGTCCACGAACCACTTATAC
ACCCACATGACCCACTTCCTAAAGCAGTGTTTCTCTTTGTCAGACTAA
Chromosome Location
2
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDQ12884
UniProtKB Entry NameSEPR_HUMAN
GenBank Gene IDBC026250
GenAtlas IDFAP
HGNC IDHGNC:3590
General References
  1. 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. [Article]
  2. 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. [Article]
  3. 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. [Article]
  4. 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. [Article]
  5. 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. [Article]
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  7. 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. Epub 2004 Jan 29. [Article]
  8. 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. [Article]
  9. 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. [Article]
  10. 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. [Article]
  11. 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. [Article]
  12. 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. [Article]
  13. 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. [Article]
  14. 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. [Article]
  15. 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. [Article]
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  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. Epub 2007 Mar 24. [Article]
  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. Epub 2007 Dec 21. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  29. Osborne B, Yao TW, Wang XM, Chen Y, Kotan LD, Nadvi NA, Herdem M, McCaughan GW, Allen JD, Yu DM, Topaloglu AK, Gorrell MD: A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation. Biochim Biophys Acta. 2014 Jul;1844(7):1248-59. doi: 10.1016/j.bbapap.2014.03.015. Epub 2014 Apr 6. [Article]
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB06474SibrotuzumabinvestigationalunknownDetails