Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive Human Tumor Stromal Fibroblasts

Abstract

Proteolytic degradation of extracellular matrix (ECM) components during tissue remodeling plays a pivotal role in normal and pathological processes including wound healing, inflammation, tumor invasion, and metastasis. Proteolytic enzymes in tumors may activate or release growth factors from the ECM or act directly on the ECM itself, thereby facilitating angiogenesis or tumor cell migration. Fibroblast activation protein (FAP) is a cell surface antigen of reactive tumor stromal fibroblasts found in epithelial cancers and in granulation tissue during wound healing. It is absent from most normal adult human tissues. FAP is conserved throughout chordate evolution, with homologues in mouse and Xenopus laevis, whose expression correlates with tissue remodeling events. Using recombinant and purified natural FAP, we show that FAP has both dipeptidyl peptidase activity and a collagenolytic activity capable of degrading gelatin and type I collagen; by sequence, FAP belongs to the serine protease family rather than the matrix metalloprotease family. Mutation of the putative catalytic serine residue of FAP to alanine abolishes both enzymatic activities. Consistent with its in vivo expression pattern determined by immunohistochemistry, FAP enzyme activity was detected by an immunocapture assay in human cancerous tissues but not in matched normal tissues. This study demonstrates that FAP is present as an active cell surface-bound collagenase in epithelial tumor stroma and opens up investigation into physiological substrates of its novel, tumorassociated dipeptidyl peptidase activity.

Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer

“…In addition to its exopeptidase activity, FAP also possesses endopeptidase activity, 30,38 making it distinct from DPP-IV. Plasma samples obtained from 27 patients were analyzed for endopeptidase activity before and during treatment in order to quantify the inhibitory effects of Val-boroPro that are more FAP selective.…”

Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4

“…Furthermore, since hDPP4 is known as a multifunctional peptidase that not only functions with hydrolase but also is involved in T-cell activation, lymphocyte-epithelial cell adhesion, and the pericellular proteolysis of the extracellular matrix (49)(50)(51)(52), bacterial DPP4 might have additional roles in periodontopathic patients. In conclusion, we propose a novel molecular mechanism of periodontitis-diabetes interaction, in which periodontopathic bacterial DPP4 adversely impacts glycemic control.…”

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…Four active members of this family are known so far: the two membrane-bound cell-surface members dipeptidyl peptidase IV (DPPIV) and the Fibroblast activation protein alpha (FaP), as well as the two soluble members DPP8 and 1 3 DPP9 (reviewed in [3][4][5][6]). Dimerization is a common feature for members of the S9B/DPPIV family [6][7][8][9][10][11] and is essential for enzymatic activity [12][13][14][15][16].…”