Details for: FAP

Gene ID: 2191

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: FAP

Ensembl ID: ENSG00000078098

Description: fibroblast activation protein alpha

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • pancreatic A cell CL0000171
    CSI 21.03
    rCSI 22.03%
    PRS 95.21
  • skin fibroblast CL0002620
    CSI 9.02
    rCSI 7.78%
    PRS 93.65
  • bronchus fibroblast of lung CL2000093
    CSI 8.79
    rCSI 7.14%
    PRS 93.87
  • fibroblast of breast CL4006000
    CSI 5.37
    rCSI 22.58%
    PRS 95.89
  • blood vessel endothelial cell CL0000071
    CSI 4.96
    rCSI 10.28%
    PRS 92.87
  • alveolar type 1 fibroblast cell CL4028004
    CSI 4.8
    rCSI 5.26%
    PRS 95.44
  • fibroblast of lung CL0002553
    CSI 4.66
    rCSI 4.34%
    PRS 95.28
  • Mueller cell CL0000636
    CSI 4.62
    rCSI 10.54%
    PRS 89.33
  • hepatic stellate cell CL0000632
    CSI 4.17
    rCSI 15.62%
    PRS 91.47
  • pancreatic stellate cell CL0002410
    CSI 3.61
    rCSI 20.99%
    PRS 95.21
  • chondrocyte CL0000138
    CSI 2.75
    rCSI 4.38%
    PRS 90.88
  • keratocyte CL0002363
    CSI 2.56
    rCSI 6.16%
    PRS 94.57
  • retinal pigment epithelial cell CL0002586
    CSI 2.41
    rCSI 4.79%
    PRS 91.53
  • mesenchymal cell CL0008019
    CSI 1.92
    rCSI 4.89%
    PRS 90.71
  • alveolar adventitial fibroblast CL4028006
    CSI 1.77
    rCSI 2.8%
    PRS 94.94
  • tendon cell CL0000388
    CSI 1.74
    rCSI 4.52%
    PRS 95.8
  • fibroblast of cardiac tissue CL0002548
    CSI 1.58
    rCSI 7.55%
    PRS 94.98
  • melanocyte of skin CL1000458
    CSI 1.56
    rCSI 2.12%
    PRS 68.96
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.36
    rCSI 3.3%
    PRS 82.94
  • blood vessel smooth muscle cell CL0019018
    CSI 0.66
    rCSI 5.36%
    PRS 93.04
  • mesenchymal stem cell CL0000134
    CSI 0.28
    rCSI 3.12%
    PRS 95.41

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.

Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Fibroblast activation protein alpha, encoded by the [FAP](/details-gene/2191) gene, is a type II transmembrane serine protease. It functions as both a dipeptidyl peptidase and a gelatinase, playing a crucial role in extracellular matrix remodeling, cell adhesion, and migration. The expression profile of [FAP](/details-gene/2191) is highly specific, with significant expression observed predominantly in activated fibroblasts and related mesenchymal cell types, such as [skin fibroblast](/details-cell/CL0002620) and [hepatic stellate cell](/details-cell/CL0000632). Its expression is characteristically upregulated in the stroma of epithelial cancers, during wound healing, and in chronic inflammation and fibrosis, making it a key player in tissue remodeling processes. An unexpectedly high significance score is also noted in [pancreatic A cell](/details-cell/CL0000171), suggesting a potential, less-characterized role in endocrine function. Clinically, its restricted expression pattern in pathological tissues has made it an attractive target for diagnostic imaging and cancer therapy. Disease association has been linked to OMIM entry [600403](https://omim.org/entry/600403). ## Cellular Roles and Expression Landscape The expression landscape of [FAP](/details-gene/2191) strongly establishes its identity as a marker of activated mesenchymal cells involved in tissue construction and remodeling. **Overall**, the gene shows the highest significance in various fibroblast populations, including [skin fibroblast](/details-cell/CL0002620) (CSI: 9.02), [bronchus fibroblast of lung](/details-cell/CL2000093) (CSI: 8.79), [fibroblast of breast](/details-cell/CL4006000) (CSI: 5.37), and specialized lung fibroblasts like [alveolar type 1 fibroblast cell](/details-cell/CL4028004) (CSI: 4.80). This pattern is consistent with its initial discovery as a protein selectively expressed in the stromal fibroblasts of epithelial cancers ([Link](https://doi.org/10.1073/pnas.91.12.5657)). Beyond canonical fibroblasts, [FAP](/details-gene/2191) is also a key marker for fibroblastic-like stellate cells, including [hepatic stellate cell](/details-cell/CL0000632) (CSI: 4.17) and [pancreatic stellate cell](/details-cell/CL0002410) (CSI: 3.61), which are central to the development of fibrosis in the liver and pancreas ([Link](https://doi.org/10.1002/hep.510290631)). Its role extends to other structural cells such as [chondrocyte](/details-cell/CL0000138) and [keratocyte](/details-cell/CL0002363), further emphasizing its function in connective tissue biology. Strikingly, the single highest significance score for [FAP](/details-gene/2191) is observed in [pancreatic A cell](/details-cell/CL0000171) (CSI: 21.03), an endocrine cell type. This exceptionally high value is atypical for a gene primarily associated with mesenchymal stroma and suggests a distinct and potentially under-investigated physiological role within pancreatic islets. The gene's notable expression in [blood vessel endothelial cell](/details-cell/CL0000071) also aligns with its documented involvement in angiogenesis. ## Pathways and Molecular Function The molecular functions attributed to [FAP](/details-gene/2191) are centered on its proteolytic capabilities. As a serine protease, it exhibits both [dipeptidyl-peptidase activity](/details-gene/GO:0008239) and [serine-type endopeptidase activity](/details-gene/GO:0004252) ([Link](https://doi.org/10.1074/jbc.274.51.36505)). These enzymatic activities enable it to participate directly in [proteolysis](/details-gene/GO:0006508), particularly in the degradation of gelatin and type I collagen, which is critical for remodeling the extracellular matrix. Functionally, these molecular activities drive several biological processes. [FAP](/details-gene/2191) is implicated in the [negative regulation of extracellular matrix disassembly](/details-gene/GO:0010716), [angiogenesis](/details-gene/GO:0001525), and [cell adhesion](/details-gene/GO:0007155), processes fundamental to wound healing, fibrosis, and tumor invasion ([Link](https://doi.org/10.1002/hep.20853)). Its expression on the [cell surface](/details-gene/GO:0009986), specifically within motile structures like the [lamellipodium](/details-gene/GO:0030027) and at [focal adhesion](/details-gene/GO:0005925) sites, positions it to physically interact with the cellular microenvironment. This localization is crucial for its role in cancer, where it is found on the invadopodia of malignant melanoma cells, promoting their invasive potential ([Link](https://doi.org/10.1073/pnas.87.21.8296)). The protein's ability to bind integrins ([integrin binding](/details-gene/GO:0005178)) further links it to the machinery of cell migration and invasion ([Link](https://doi.org/10.1074/jbc.274.35.24947)). ## Research Directions The expression profile and functional annotation of [FAP](/details-gene/2191) confirm its established role in stromal activation while also highlighting new avenues for investigation. The data suggests several testable hypotheses. 1. **Hypothesis 1:** The exceptionally high and specific significance of [FAP](/details-gene/2191) in [pancreatic A cell](/details-cell/CL0000171) is not related to stromal remodeling but rather to a cell-intrinsic function, such as the proteolytic processing of proglucagon or other islet-related peptides, or the regulation of alpha-cell turnover and survival. 2. **Hypothesis 2:** During the progression of lung fibrosis, the enzymatic activity of [FAP](/details-gene/2191) expressed by [bronchus fibroblast of lung](/details-cell/CL2000093) and [alveolar adventitial fibroblast](/details-cell/CL4028006) is a primary driver of pathological matrix deposition, and its inhibition could reverse or halt fibrotic remodeling. 3. **Hypothesis 3:** In epithelial cancers, [FAP](/details-gene/2191) on cancer-associated fibroblasts facilitates tumor angiogenesis not only by remodeling the matrix but also by directly cleaving and activating pro-angiogenic factors sequestered in the tumor microenvironment. **Experimental Proposal for Hypothesis 1:** To elucidate the non-canonical role of [FAP](/details-gene/2191) in pancreatic alpha cells, a multi-pronged approach is warranted. Initially, immunofluorescence co-staining for FAP and glucagon in human pancreatic tissue sections would confirm its specific localization to alpha cells. Subsequently, a conditional knockout mouse model, deleting [FAP](/details-gene/2191) specifically in glucagon-expressing cells, should be created. These mice could then be subjected to metabolic challenges (e.g., glucose tolerance tests, fasting) to assess for defects in glucose homeostasis and glucagon secretion. Mass spectrometry-based proteomics on isolated islets from these knockout mice could then be used to identify changes in the processing of proglucagon and other potential peptide substrates. **Therapeutic Potential:** [FAP](/details-gene/2191) represents an outstanding therapeutic target due to its high expression in the microenvironment of various pathologies, including cancer and fibrosis, with minimal expression in healthy adult organs. Its presence on the cell surface makes it readily accessible for targeted therapies. The primary strategy is **inhibition** of its enzymatic activity or **elimination** of FAP-expressing cells. This has led to the clinical development of FAP-inhibitors, FAP-targeted antibody-drug conjugates (ADCs), radioligand therapies, and chimeric antigen receptor (CAR)-T cells, which have shown promising results in targeting tumor stroma and reducing its pro-tumorigenic effects.

Genular Protein ID: 3955094465

Symbol: SEPR_HUMAN

Name: N/A

UniProtKB Accession Codes:

Database IDs:

Citations:

PubMed ID: 7911242

Title: Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers.

PubMed ID: 7911242

DOI: 10.1073/pnas.91.12.5657

PubMed ID: 9247085

Title: Molecular cloning of seprase: a serine integral membrane protease from human melanoma.

PubMed ID: 9247085

DOI: 10.1016/s0925-4439(97)00032-x

PubMed ID: 9065413

Title: Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease.

PubMed ID: 9065413

DOI: 10.1074/jbc.272.12.7595

PubMed ID: 10644713

Title: Identification of an alternatively spliced seprase mRNA that encodes a novel intracellular isoform.

PubMed ID: 10644713

DOI: 10.1074/jbc.275.4.2554

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 14751930

Title: A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion.

PubMed ID: 14751930

DOI: 10.1182/blood-2003-12-4240

PubMed ID: 7519584

Title: Fibroblast activation protein: purification, epitope mapping and induction by growth factors.

PubMed ID: 7519584

DOI: 10.1002/ijc.2910580314

PubMed ID: 2172980

Title: A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells.

PubMed ID: 2172980

DOI: 10.1073/pnas.87.21.8296

PubMed ID: 7923219

Title: A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells.

PubMed ID: 7923219

PubMed ID: 10347120

Title: Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis.

PubMed ID: 10347120

DOI: 10.1002/hep.510290631

PubMed ID: 10593948

Title: Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts.

PubMed ID: 10593948

DOI: 10.1074/jbc.274.51.36505

PubMed ID: 10455171

Title: A novel protease-docking function of integrin at invadopodia.

PubMed ID: 10455171

DOI: 10.1074/jbc.274.35.24947

PubMed ID: 12376466

Title: Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton.

PubMed ID: 12376466

DOI: 10.1093/carcin/23.10.1593

PubMed ID: 16175601

Title: Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line.

PubMed ID: 16175601

DOI: 10.1002/hep.20853

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 17105646

Title: Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes.

PubMed ID: 17105646

DOI: 10.1186/ar2080

PubMed ID: 16223769

Title: Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein.

PubMed ID: 16223769

DOI: 10.1182/blood-2005-08-3452

PubMed ID: 16651416

Title: The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices.

PubMed ID: 16651416

DOI: 10.1158/0008-5472.can-05-1245

PubMed ID: 16480718

Title: Peptide substrate profiling defines fibroblast activation protein as an endopeptidase of strict Gly(2)-Pro(1)-cleaving specificity.

PubMed ID: 16480718

DOI: 10.1016/j.febslet.2006.01.087

PubMed ID: 16410248

Title: Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity.

PubMed ID: 16410248

DOI: 10.1074/jbc.m511112200

PubMed ID: 17381073

Title: Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization.

PubMed ID: 17381073

DOI: 10.1021/bi062227y

PubMed ID: 18095711

Title: Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites.

PubMed ID: 18095711

DOI: 10.1021/bi701921b

PubMed ID: 18262497

Title: Seprase: an overview of an important matrix serine protease.

PubMed ID: 18262497

DOI: 10.1016/j.bbapap.2008.01.006

PubMed ID: 20707604

Title: Expression and role of the cell surface protease seprase/fibroblast activation protein-alpha (FAP-alpha) in astroglial tumors.

PubMed ID: 20707604

DOI: 10.1515/bc.2010.119

PubMed ID: 21314817

Title: Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-alpha.

PubMed ID: 21314817

DOI: 10.1111/j.1742-4658.2011.08051.x

PubMed ID: 21288888

Title: Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate.

PubMed ID: 21288888

DOI: 10.1093/jb/mvr017

PubMed ID: 24371721

Title: Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs.

PubMed ID: 24371721

DOI: 10.1016/j.fob.2013.12.001

PubMed ID: 24717288

Title: A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation.

PubMed ID: 24717288

DOI: 10.1016/j.bbapap.2014.03.015

PubMed ID: 15809306

Title: Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha.

PubMed ID: 15809306

DOI: 10.1074/jbc.c500092200

Sequence Information:

  • Length: 760
  • Mass: 87713
  • Checksum: 7FF817B5A4F75142
  • Sequence:
  • MKTWVKIVFG VATSAVLALL VMCIVLRPSR VHNSEENTMR ALTLKDILNG TFSYKTFFPN 
    WISGQEYLHQ SADNNIVLYN IETGQSYTIL SNRTMKSVNA SNYGLSPDRQ FVYLESDYSK 
    LWRYSYTATY YIYDLSNGEF VRGNELPRPI QYLCWSPVGS KLAYVYQNNI YLKQRPGDPP 
    FQITFNGREN KIFNGIPDWV YEEEMLATKY ALWWSPNGKF LAYAEFNDTD IPVIAYSYYG 
    DEQYPRTINI PYPKAGAKNP VVRIFIIDTT YPAYVGPQEV PVPAMIASSD YYFSWLTWVT 
    DERVCLQWLK RVQNVSVLSI CDFREDWQTW DCPKTQEHIE ESRTGWAGGF FVSTPVFSYD 
    AISYYKIFSD KDGYKHIHYI KDTVENAIQI TSGKWEAINI FRVTQDSLFY SSNEFEEYPG 
    RRNIYRISIG SYPPSKKCVT CHLRKERCQY YTASFSDYAK YYALVCYGPG IPISTLHDGR 
    TDQEIKILEE NKELENALKN IQLPKEEIKK LEVDEITLWY KMILPPQFDR SKKYPLLIQV 
    YGGPCSQSVR SVFAVNWISY LASKEGMVIA LVDGRGTAFQ GDKLLYAVYR KLGVYEVEDQ 
    ITAVRKFIEM GFIDEKRIAI WGWSYGGYVS SLALASGTGL FKCGIAVAPV SSWEYYASVY 
    TERFMGLPTK DDNLEHYKNS TVMARAEYFR NVDYLLIHGT ADDNVHFQNS AQIAKALVNA 
    QVDFQAMWYS DQNHGLSGLS TNHLYTHMTH FLKQCFSLSD

Genular Protein ID: 3398505832

Symbol: B4DLR2_HUMAN

Name: N/A

UniProtKB Accession Codes:

Database IDs:

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

Sequence Information:

  • Length: 735
  • Mass: 84862
  • Checksum: A6ABE4083721544D
  • Sequence:
  • MKTWVKIVFG VATSAVLALL VMCIVLRPSR VHNSEENTMR ALTLKDILNG TFSYKTFFPN 
    WISGQEYLHQ SADNNIVLYN IETGQSYTIL SNRTMLWRYS YTATYYIYDL SNGEFVRGNE 
    LPRPIQYLCW SPVGSKLAYV YQNNIYLKQR PGDPPFQITF NGRENKIFNG IPDWVYEEEM 
    LATKYALWWS PNGKFLAYAE FNDTDIPVIA YSYYGDEQYP RTINIPYPKA GAKNPVVRIF 
    IIDTTYPAYV GPQEVPVPAM IASSDYYFSW LTWVTDERVC LQWLKRVQNV SVLSICDFRE 
    DWQTWDCPKT QEHIEESRTG WAGGFFVSTP VFSYDAISYY KIFSDKDGYK HIHYIKDTVE 
    NAIQITSGKW EAINIFRVTQ DSLFYSSNEF EEYPGRRNIY RISIGSYPPS KKCVTCHLRK 
    ERCQYYTASF SDYAKYYALV CYGPGIPIST LHDGRTDQEI KILEENKELE NALKNIQLPK 
    EEIKKLEVDE ITLWYKMILP PQFDRSKKYP LLIQVYGGPC SQSVRSVFAV NWISYLASKE 
    GMVIALVDGR GTAFQGDKLL YAVYRKLGVY EVEDQITAVR KFIEMGFIDE KRIAIWGWSY 
    GGYVSSLALA SGTGLFKCGI AVAPVSSWEY YASVYTERFM GLPTKDDNLE HYKNSTVMAR 
    AEYFRNVDYL LIHGTADDNV HFQNSAQIAK ALVNAQVDFQ AMWYSDQNHG LSGLSTNHLY 
    THMTHFLKQC FSLSD