Biomedical Engineering Reference
In-Depth Information
5.3.4 Substrates of FAP
FAP has both dipeptidyl peptidase activity and endopeptidase activity. No
physiological dipeptidyl peptidase substrates of FAP have been identified.
However, the presence of conserved key residues around the active site suggests
that FAP could cleave some DPP-4 substrates.
The endopeptidase activity of FAP includes gelatinase activity (cleavage of
denatured collagen), with specificity for type I collagen.
119,120,123
The extent of
collagen denaturation needed to permit FAP cleavage needs further clarifica-
tion. This gelatinase activity suggests that FAP could have a role in ECM
degradation. FAP may also work with other proteases to cleave denatured or
partially degraded collagen fragments during ECM remodeling. Indeed, fol-
lowing partial collagen cleavage by matrix metalloproteinase-1 (MMP-1), FAP
can cleave collagen I and III into smaller fragments.
149
Unlike MMPs which
have a proenzyme form, the activity of FAP is constitutive.
120
Recently, a study of FAP cleavage sites within recombinant human collagen
I-derived gelatin identified potential consensus cleavage sequences including
Pro-Pro-Gly-Pro and (Asp/Glu)-(Arg/Lys)-Gly-(Glu/Asp)-(Thr/Ser)-Gly-
Pro.
126
However, although earlier studies suggested a strict requirement of Gly-
Pro for FAP hydrolysis,
122,148
this study indicated that FAP can also cleave
peptides containing other amino acids in the P1 position, including Ala, Arg,
Asp, Lys, and Ser.
126
Human a2-antiplasmin is an important physiological FAP substrate. Blood
coagulation is central to tissue repair, resulting in fibrin deposition, and this
fibrin clot is lysed primarily by plasmin. The function of a2-antiplasmin is to
protect fibrin from premature cleavage by plasmin. Liver cells secrete a2-
antiplasmin as a single-chain glycoprotein.
124
Circulating soluble FAP removes
an N-terminal 12-residue peptide from a2-antiplasmin by cleavage between
Pro
12
and Asn
13
, causing conversion to a more active form, Asn-a2-anti-
plasmin.
125,150
Hence, a selective FAP inhibitor might increase fibrinolysis and
thereby enhance wound healing and reduce adhesions. Rodent a2-antiplasmin
lacks Pro at or near position 12 and appears not to have an alternate FAP
cleavage site, so related studies in rodents cannot be attempted.
5.3.5 Targeting FAP for Cancer Therapy
While details of the complete functions, substrates, and ligands of FAP have
yet to be fully characterized, its expression on activated stromal fibroblasts in
many types of cancers has resulted in numerous studies on the potential use of
FAP as a therapeutic target in tumors. The limited distribution of FAP,
whereby it is specifically overexpressed in most solid tumors and not in normal
adult tissue, allows for therapeutic approaches to treat a number of different
malignancies, in contrast to therapies involving antigens that are expressed
solely by specific tumor types. Moreover, tumor cells are genetically unstable,
whereas stromal fibroblasts are genetically stable and so are a relatively sta-
tionary target. Therapies targeting FAP would be delivered to the specific site
