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J Biol Chem, Vol. 274, Issue 51, 36505-36512, December 17, 1999
From the 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,
tumor-associated dipeptidyl peptidase activity.
Fibroblast Activation Protein, a Dual Specificity Serine Protease
Expressed in Reactive Human Tumor Stromal Fibroblasts*
§,,,,
Department of Oncology Research, Boehringer
Ingelheim Pharma KG, Birkendorferstrasse 65, 88397 Biberach, Germany
and the ¶ Ludwig Institute for Cancer Research, New York Branch,
Memorial Sloan-Kettering Cancer Center,
New York, New York 10021
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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