Fibroblast activation protein, alpha

Fibroblast activation protein, alpha
PDB rendering based on 1z68.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1Z68​
Identifiers
Symbols	FAP ; DPPIV; FAPA; SIMP
External IDs	OMIM: 600403 MGI: 109608 HomoloGene: 48282 ChEMBL: 4683 GeneCards: FAP Gene
EC number	3.4.14.5, 3.4.21.26
Gene ontology Molecular function • protease binding • endopeptidase activity • metalloendopeptidase activity • serine-type endopeptidase activity • integrin binding • protein binding • peptidase activity • serine-type peptidase activity • dipeptidyl-peptidase activity • protein homodimerization activity • protein dimerization activity Cellular component • extracellular space • cytoplasm • plasma membrane • focal adhesion • cell surface • integral component of membrane • lamellipodium • lamellipodium membrane • ruffle membrane • apical part of cell • basal part of cell • invadopodium membrane Biological process • angiogenesis • proteolysis • cell adhesion • regulation of collagen catabolic process • negative regulation of extracellular matrix disassembly • endothelial cell migration • proteolysis involved in cellular protein catabolic process • regulation of fibrinolysis • negative regulation of cell proliferation involved in contact inhibition • positive regulation of cell cycle arrest • mitotic cell cycle arrest • melanocyte proliferation • positive regulation of execution phase of apoptosis • melanocyte apoptotic process • negative regulation of extracellular matrix organization 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_001291807	NM_007986
RefSeq (protein)	NP_001278736	NP_032012
Location (UCSC)	Chr 2: 162.17 – 162.25 Mb	Chr 2: 62.5 – 62.57 Mb
PubMed search

Fibroblast activation protein alpha is a 170 kDa melanoma membrane-bound gelatinase, protein that in humans is encoded by the FAP gene.^[1]

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.^[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 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 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.

References

1. "Entrez Gene: fibroblast activation protein, alpha".
2. "Merops: the peptidase database".
3. The Tumor Microenvironment as a Drug Target: Chasing Slippery Targets
4. 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. PMID 15809306.

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. PMID 7519584.
• 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. PMID 7774951.
• Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, Old LJ, Rettig WJ (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.
• 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. PMID 9065413.
• 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. 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, 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. 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.
• 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. ISBN 0-306-47717-3. PMID 12675244.
• 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. PMID 12926053.
• 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. 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.
• 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. PMID 14707457.
• Cheng JD, Valianou M, Canutescu AA, Jaffe EK, Lee HO, Wang H, Lai JH, Bachovchin WW, Weiner LM (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 2015-01-01). PMID 15767544.
• 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. PMID 15809306.
• 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. PMID 16061874.