The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromalfibroblasts 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.[1]
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.[2] 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.
As of April 2013[update] The endogenous substrates of FAP have not yet been identified.[3]
Structure
Fibroblast activation protein is a homodimeric integral protein with dipeptidyl peptidase IV (DPPIV)-like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.[4]
Clinical significance
FAP expression is seen on activated stromal fibroblasts of more than 90% of all human carcinomas. 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 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.
↑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". J. Biol. Chem. 280 (20): 19441–4. doi:10.1074/jbc.C500092200. PMID15809306.
Further reading
Rettig WJ, Su SL, Fortunato SR, Scanlan MJ, Raj BK, Garin-Chesa P, Healey JH, Old LJ (1994). "Fibroblast activation protein: purification, epitope mapping and induction by growth factors". Int. J. Cancer. 58 (3): 385–92. doi:10.1002/ijc.2910580314. PMID7519584.
Mathew S, Scanlan MJ, Mohan Raj BK, Murty VV, Garin-Chesa P, Old LJ, Rettig WJ, Chaganti RS (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. PMID7774951.
Piñeiro-Sánchez ML, Goldstein LA, Dodt J, Howard L, Yeh Y, Tran H, Argraves WS, Chen WT (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. PMID9065413.
Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, Salamone M, Yeh Y, Flessate D, Chen WT (1997). "Molecular cloning of seprase: a serine integral membrane protease from human melanoma". Biochim. Biophys. Acta. 1361 (1): 11–9. doi:10.1016/s0925-4439(97)00032-x. PMID9247085.
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. PMID10644713.
Ghersi G, Dong H, Goldstein LA, Yeh Y, Hakkinen L, Larjava HS, Chen WT (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. PMID12023964.
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. PMID12028401.
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. PMID12376466.
Gorrell MD, Wang XM, Levy MT, Kable E, Marinos G, Cox G, McCaughan GW (2003). "Intrahepatic expression of collagen and fibroblast activation protein (FAP) in hepatitis C virus infection". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 524: 235–43. doi:10.1007/0-306-47920-6_28. ISBN0-306-47717-3. PMID12675244.
Jin X, Iwasa S, Okada K, Mitsumata M, Ooi A (2003). "Expression patterns of seprase, a membrane serine protease, in cervical carcinoma and cervical intraepithelial neoplasm". Anticancer Res. 23 (4): 3195–8. PMID12926053.
Iwasa S, Jin X, Okada K, Mitsumata M, Ooi A (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. PMID12963128.
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. PMID14524536.
Okada K, Chen WT, Iwasa S, Jin X, Yamane T, Ooi A, Mitsumata M (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. PMID14707457.
Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, Zhang Y, Kraus ML, Salakian S, Sridhar V, Wijnands R, Tennant MG (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. PMID15809306.
Fassnacht M, Lee J, Milazzo C, Boczkowski D, Su Z, Nair S, Gilboa E (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. PMID16061874.
