Fibroblast activation protein, alpha

Fibroblast activation protein, alpha
PDB rendering based on 1z68.
Available structures PDB 1z68
Identifiers
Symbols	FAP; DKFZp686G13158; DPPIV; FAPA
External IDs	OMIM: 600403 MGI: 109608 HomoloGene: 48282 GeneCards: FAP Gene
EC number	3.4.21.-
Gene Ontology Molecular function • metalloendopeptidase activity • serine-type endopeptidase activity • protein binding • peptidase activity • serine-type peptidase activity • serine-type peptidase activity • serine-type peptidase activity • dipeptidyl-peptidase activity • protein homodimerization activity • protein dimerization activity Cellular component • plasma membrane • integral to membrane • lamellipodium • cell junction • lamellipodium membrane • invadopodium membrane Biological process • proteolysis • negative regulation of extracellular matrix disassembly • endothelial cell migration Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2191	14089
Ensembl	ENSG00000078098	ENSMUSG00000000392
UniProt	Q12884	P97321
RefSeq (mRNA)	NM_004460	NM_007986.2
RefSeq (protein)	NP_004451	NP_032012.1
Location (UCSC)	Chr 2: 163.03 – 163.1 Mb	Chr 2: 62.34 – 62.41 Mb
PubMed search	[1]	[2]

Fibroblast activation protein, alpha (FAP) also known as seprase or 170 kDa melanoma membrane-bound gelatinase is a protein that in humans is encoded by the FAP gene.

Function

The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. This protein is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.

FAP, also known as seprase, belongs to the clan SC proteases and is a member of the S9B prolyl oligopeptidase subfamily. Other members of the S9B subfamily are DPPIV, DPP8 and DPP9. FAP is most closely related to DPPIV and they share about 50% of their amino acids.

FAP is catalytically active as a 170kD dimer and has dipeptidase and gelatinase activity. Its gelatinase activity requires a glycine in P2 position.

Structure

Fibroblast activation protein is a hemodimeric integral protein with dipeptidyl peptidase IV (DPPIV)-like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.

Clinical significance

FAP expression is seen on activated stromal fibroblasts of more than 90% of all human carcinomes. Stromal fibroblasts play an important role in the development, growth and metastasis of carcinomas.

It has been shown that targeting FAP inhibits stromagenesis and growth of tumor in mice.

Talabostat is a 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.

Further reading

• Rettig WJ, Su SL, Fortunato SR, et al. (1994). "Fibroblast activation protein: purification, epitope mapping and induction by growth factors.". Int. J. Cancer 58 (3): 385–92. doi:10.1002/ijc.2910580314. PMID 7519584. 
• Mathew S, Scanlan MJ, Mohan Raj BK, et al. (1995). "The gene for fibroblast activation protein alpha (FAP), a putative cell surface-bound serine protease expressed in cancer stroma and wound healing, maps to chromosome band 2q23.". Genomics 25 (1): 335–7. doi:10.1016/0888-7543(95)80157-H. PMID 7774951. 
• Scanlan MJ, Raj BK, Calvo B, et al. (1994). "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. 91 (12): 5657–61. doi:10.1073/pnas.91.12.5657. PMC 44055. PMID 7911242. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=44055. 
• Piñeiro-Sánchez ML, Goldstein LA, Dodt J, et al. (1997). "Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease.". J. Biol. Chem. 272 (12): 7595–601. doi:10.1074/jbc.272.12.7595. PMID 9065413. 
• Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, et al. (1997). "Molecular cloning of seprase: a serine integral membrane protease from human melanoma.". Biochim. Biophys. Acta 1361 (1): 11–9. PMID 9247085. 
• Goldstein LA, Chen WT (2000). "Identification of an alternatively spliced seprase mRNA that encodes a novel intracellular isoform.". J. Biol. Chem. 275 (4): 2554–9. doi:10.1074/jbc.275.4.2554. PMID 10644713. 
• Ghersi G, Dong H, Goldstein LA, et al. (2002). "Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex.". J. Biol. Chem. 277 (32): 29231–41. doi:10.1074/jbc.M202770200. PMID 12023964. 
• Levy MT, McCaughan GW, Marinos G, Gorrell MD (2002). "Intrahepatic expression of the hepatic stellate cell marker fibroblast activation protein correlates with the degree of fibrosis in hepatitis C virus infection.". Liver 22 (2): 93–101. doi:10.1034/j.1600-0676.2002.01503.x. PMID 12028401. 
• Artym VV, Kindzelskii AL, Chen WT, Petty HR (2002). "Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton.". Carcinogenesis 23 (10): 1593–601. doi:10.1093/carcin/23.10.1593. PMID 12376466. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Gorrell MD, Wang XM, Levy MT, et al. (2003). "Intrahepatic expression of collagen and fibroblast activation protein (FAP) in hepatitis C virus infection.". Adv. Exp. Med. Biol. 524: 235–43. doi:10.1007/0-306-47920-6_28. PMID 12675244. 
• Jin X, Iwasa S, Okada K, et al. (2003). "Expression patterns of seprase, a membrane serine protease, in cervical carcinoma and cervical intraepithelial neoplasm.". Anticancer Res. 23 (4): 3195–8. PMID 12926053. 
• Iwasa S, Jin X, Okada K, et al. (2003). "Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer.". Cancer Lett. 199 (1): 91–8. doi:10.1016/S0304-3835(03)00315-X. PMID 12963128. 
• Goodman JD, Rozypal TL, Kelly T (2003). "Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells.". Clin. Exp. Metastasis 20 (5): 459–70. doi:10.1023/A:1025493605850. PMID 14524536. 
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
• Okada K, Chen WT, Iwasa S, et al. (2004). "Seprase, a membrane-type serine protease, has different expression patterns in intestinal- and diffuse-type gastric cancer.". Oncology 65 (4): 363–70. doi:10.1159/000074650. PMID 14707457. 
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928. 
• Cheng JD, Valianou M, Canutescu AA, et al. (2005). "Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth.". Mol. Cancer Ther. 4 (3): 351–60. doi:10.1158/1535-7163.MCT-04-0269 (inactive 2008-10-03). PMID 15767544. http://mct.aacrjournals.org/content/4/3/351.abstract. 
• Aertgeerts K, Levin I, Shi L, et al. (2005). "Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha.". J. Biol. Chem. 280 (20): 19441–4. doi:10.1074/jbc.C500092200. PMID 15809306. 
• Fassnacht M, Lee J, Milazzo C, et al. (2006). "Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy.". Clin. Cancer Res. 11 (15): 5566–71. doi:10.1158/1078-0432.CCR-05-0699. PMID 16061874.