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Fibroblast activation protein, alpha

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(Redirected from Seprase)
FAP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFAP, DPPIV, FAPA, SIMP, fibroblast activation protein alpha, FAPalpha
External IDsOMIM: 600403; MGI: 109608; HomoloGene: 48282; GeneCards: FAP; OMA:FAP - orthologs
EC number3.4.14.5
Orthologs
SpeciesHumanMouse
Entrez

2191

14089

Ensembl

ENSG00000078098

ENSMUSG00000000392

UniProt

Q12884

P97321

RefSeq (mRNA)

NM_001291807
NM_004460

NM_007986

RefSeq (protein)

NP_001278736
NP_004451

NP_032012

Location (UCSC)Chr 2: 162.17 – 162.25 MbChr 2: 62.33 – 62.4 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fibroblast activation protein alpha (FAP-alpha) also known as prolyl endopeptidase FAP is an enzyme that in humans is encoded by the FAP gene.[5]

Prolyl endopeptidase FAP is a 170 kDa membrane-bound gelatinase. It was independently identified as a surface glycoprotein recognized by the F19 monoclonal antibody in activated fibroblasts[6] and a Surface Expressed Protease (seprase) in invasive melanoma cells.[7][8]

Structure and enzymatic activity

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FAP is a 760 amino acid long type II transmembrane glycoprotein. It contains a very short cytoplasmic N terminal part (6 amino acids), a transmembrane region (amino acids 7–26), and a large extracellular part with an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.[9][10]

A soluble form of FAP, which lacks the intracellular and transmembrane part, is present in blood plasma.[11] FAP is a non-classical serine protease, which belongs to the S9B prolyl oligopeptidase subfamily. Other members of the S9B subfamily are DPPIV, DPP8 and DPP9.[12] FAP is most closely related to DPPIV (approximately 50% of their amino acids are identical). The active site of FAP is localized in the extracellular part of the protein and contains a catalytic triad composed of Ser624 Asp702 His734 in humans and mice.[10] FAP is catalytically active as a 170kD homodimer and has a dipeptidase and an endopeptidase activity.

Several bioactive peptides and structural proteins were reported to be cleaved by FAP, such as neuropeptide Y (NPY), Peptide YY, Substance P (SP), and B-type natriuretic peptide (BNP),[13] human fibroblast growth factor 21 (FGF-21), human alpha2 antiplasmin and denatured collagen I and III. NPY, FGF-21 and alpha2 antiplasmin are considered to be physiological FAP substrates.[14][15]

Expression and possible function

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FAP expression under physiological conditions is very low in the majority of adult tissues. FAP is nevertheless expressed during embryonic development,[16] and in adults in pancreatic alpha cells[17] in multipotent bone marrow stromal cells (BM-MSC)[18] and uterine stroma.[19]

FAP expression is high in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. FAP is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.[5]

Clinical significance

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FAP expression is seen on activated stromal fibroblasts of more than 90% of all human carcinomas.[14][15] Stromal fibroblasts play an important role in the development, growth and metastasis of carcinomas. Several approaches of FAP targeting mainly in cancer treatment are currently being tested including the use of low molecular weight inhibitors, prodrugs activated by FAP, various anti-FAP antibodies and their conjugates, FAP-CAR T cells, and FAP vaccines.[15]

By cleaving FGF-21, FAP is also thought to play a possible role in energy metabolism.[20]

Talabostat is an inhibitor of FAP and related enzymes, for which clinical trials have been done, but further research is suspended.

Sibrotuzumab is a monoclonal antibody against FAP.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000078098 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000392 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: fibroblast activation protein, alpha".
  6. ^ Garin-Chesa P, Old LJ, Rettig WJ (September 1990). "Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers". Proceedings of the National Academy of Sciences of the United States of America. 87 (18): 7235–9. Bibcode:1990PNAS...87.7235G. doi:10.1073/pnas.87.18.7235. PMC 54718. PMID 2402505.
  7. ^ Monsky WL, Lin CY, Aoyama A, Kelly T, Akiyama SK, Mueller SC, Chen WT (November 1994). "A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells". Cancer Research. 54 (21): 5702–10. PMID 7923219.
  8. ^ Aoyama A, Chen WT (November 1990). "A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells". Proceedings of the National Academy of Sciences of the United States of America. 87 (21): 8296–300. Bibcode:1990PNAS...87.8296A. doi:10.1073/pnas.87.21.8296. PMC 54942. PMID 2172980.
  9. ^ PDB: 1Z68​; Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, Zhang Y, Kraus ML, Salakian S, Sridhar V, Wijnands R, Tennant MG (May 2005). "Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha". The Journal of Biological Chemistry. 280 (20): 19441–4. doi:10.1074/jbc.C500092200. PMID 15809306. S2CID 25810686.
  10. ^ a b Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, Salamone M, Yeh Y, Flessate D, Chen WT (July 1997). "Molecular cloning of seprase: a serine integral membrane protease from human melanoma". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1361 (1): 11–9. doi:10.1016/S0925-4439(97)00032-X. PMID 9247085.
  11. ^ Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun JG, McKee PA (February 2006). "Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein". Blood. 107 (4): 1397–404. doi:10.1182/blood-2005-08-3452. PMID 16223769. S2CID 17654245.
  12. ^ "Merops: the peptidase database". Archived from the original on 2006-11-14. Retrieved 2009-10-05.
  13. ^ Keane FM, Nadvi NA, Yao TW, Gorrell MD (April 2011). "Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α". The FEBS Journal. 278 (8): 1316–32. doi:10.1111/j.1742-4658.2011.08051.x. PMID 21314817. S2CID 33826473.
  14. ^ a b Puré E, Blomberg R (August 2018). "Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics". Oncogene. 37 (32): 4343–4357. doi:10.1038/s41388-018-0275-3. PMC 6092565. PMID 29720723.
  15. ^ a b c Busek P, Mateu R, Zubal M, Kotackova L, Sedo A (June 2018). "Targeting fibroblast activation protein in cancer - Prospects and caveats". Frontiers in Bioscience. 23 (10): 1933–1968. doi:10.2741/4682. PMID 29772538.
  16. ^ Niedermeyer J, Garin-Chesa P, Kriz M, Hilberg F, Mueller E, Bamberger U, Rettig WJ, Schnapp A (April 2001). "Expression of the fibroblast activation protein during mouse embryo development". The International Journal of Developmental Biology. 45 (2): 445–7. PMID 11330865.
  17. ^ Busek P, Hrabal P, Fric P, Sedo A (May 2015). "Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-IV in the adult human Langerhans islets". Histochemistry and Cell Biology. 143 (5): 497–504. doi:10.1007/s00418-014-1292-0. PMID 25361590. S2CID 788806.
  18. ^ Bae S, Park CW, Son HK, Ju HK, Paik D, Jeon CJ, Koh GY, Kim J, Kim H (September 2008). "Fibroblast activation protein alpha identifies mesenchymal stromal cells from human bone marrow". British Journal of Haematology. 142 (5): 827–30. doi:10.1111/j.1365-2141.2008.07241.x. PMID 18510677. S2CID 40643695.
  19. ^ Dolznig H, Schweifer N, Puri C, Kraut N, Rettig WJ, Kerjaschki D, Garin-Chesa P (August 2005). "Characterization of cancer stroma markers: in silico analysis of an mRNA expression database for fibroblast activation protein and endosialin". Cancer Immunity. 5: 10. PMID 16076089.
  20. ^ Sánchez-Garrido MA, Habegger KM, Clemmensen C, Holleman C, Müller TD, Perez-Tilve D, Li P, Agrawal AS, Finan B, Drucker DJ, Tschöp MH, DiMarchi RD, Kharitonenkov A (October 2016). "Fibroblast activation protein (FAP) as a novel metabolic target". Molecular Metabolism. 5 (10): 1015–1024. doi:10.1016/j.molmet.2016.07.003. PMC 5034526. PMID 27689014.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: Q12884 (Human Prolyl endopeptidase FAP) at the PDBe-KB.
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