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

Lee, Kyung N.; Jackson, Kenneth W.; Christiansen, Victoria J.; Lee, Chung S.; Chun, Jin-Geun; McKee, Patrick A.

doi:10.1182/blood-2005-08-3452

Cited by 166 publications

(148 citation statements)

References 39 publications

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“…It shows the enzyme to have an active-site within a tube-like structure that courses through each monomeric half with apertures of 14 and 24 diameters at the ends of each tube. Although previously stated that FAP or its derivatives do not circulate in blood [6], we concluded that plasma APCE, which lacks the cytoplasmic tail and transmembrane sequence of FAP, may indeed result from FAP [7], possibly as a consequence of unidentified cell membrane "sheddase" activity as occurs with certain other membrane peptidases [8;9], or that it might be synthesized and secreted as a non-membrane-bound variant of FAP. To date Met-α 2 AP is the only definitive physiologic substrate identified for native APCE, and it is also cleaved by recombinant FAP [1;7].…”

Section: Introductionmentioning

confidence: 66%

“…Purification of APCE and expression and purification of recombinant FAP APCE was isolated from citrated human plasma (Sylvan Goldman Blood Institute, Oklahoma City, OK) by sequential chromatographic steps as previously described [7]. A soluble form of recombinant human FAP beginning at residue 35 was expressed by Pichia pastoris and purified from culture media as previously described [7].…”

Section: Methodsmentioning

confidence: 99%

“…A soluble form of recombinant human FAP beginning at residue 35 was expressed by Pichia pastoris and purified from culture media as previously described [7].…”

Section: Methodsmentioning

confidence: 99%

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Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen Types I, III, and IV

Christiansen

Jackson

Lee

et al. 2007

Archives of Biochemistry and Biophysics

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110

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The circulating enzyme, α 2 -antiplasmin cleaving enzyme (APCE), has very similar sequence homology and proteolytic specificity as fibroblast activation protein (FAP), a membrane-bound proteinase. FAP is expressed on activated fibroblasts associated with rapid tissue growth as in embryogenesis, wound healing, and epithelial-derived malignancies, but not in normal tissues. Its presence on stroma suggests that FAP functions to remodel extracellular matrix (ECM) during neoplastic growth. Precise biologic substrates have not been defined for FAP, although like APCE, it cleaves α 2 -antiplasmin to a derivative more easily crosslinked to fibrin. While FAP has been shown to cleave gelatin, evidence for cleavage of native collagen, the major ECM component, remains indistinct. We examined the potential proteolytic effects of FAP or APCE alone and in concert with selected matrix metalloproteinases (MMPs) on collagens I, III and IV. SDS-PAGE analyses demonstrated that neither FAP nor APCE cleaves collagen I. Following collagen I cleavage by MMP-1, however, FAP or APCE digested collagen I into smaller peptides. These peptides were analogous to, yet different from, those produced by MMP-9 following MMP-1 cleavage. Aminoterminal sequencing and mass spectrometry analyses of digestion mixtures identified several peptide fragments within the sequences of the two collagen chains. The proteolytic synergy of APCE in the cleavage of collagen I and III was not observed with collagen IV. We conclude that FAP works in synchrony with other proteinases to cleave partially degraded or denatured collagen I and III as ECM is excavated, and that derivative peptides might function to regulate malignant cell growth and motility.

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Section: Introductionmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

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Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen Types I, III, and IV

Christiansen

Jackson

Lee

et al. 2007

Archives of Biochemistry and Biophysics

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110

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“…The soluble form of FAP, or antiplasmin cleaving enzyme (APCE), has been shown to cleave the long form of antiplasmin (Met-a 2 AP) to its more active form (Asn-a 2 AP). 39 We hypothesized that if treatment inhibited FAP endopeptidase activity, greater concentrations of Met-a 2 AP would be seen in the plasma with Val-boroPro treatment. Total a 2 AP was purified from patient plasma samples collected before starting treatment and after one week of treatment.…”

Section: Resultsmentioning

confidence: 99%

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

Narra¹,

Mullins²,

Lee³

et al. 2007

Cancer Biology & Therapy

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218

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Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer.Methods: Patients with metastatic colorectal cancer who had previously received systemic chemotherapies were treated with single agent Val-boroPro 200 μg p.o. BID continuously. Eligibility included measurable disease, performance status of 0 to 2, and adequate organ function. Laboratory correlates evaluated the pharmacodynamic effects of Val-boroPro on FAP enzymatic function in the peripheral blood.Results: Twenty-eight patients (median age 62; 12 males, 16 females) were enrolled in this study. There were no objective responses. Six of 28 (21%) patients had stable disease for a median of 25 weeks (range 11-38 weeks). Laboratory analysis demonstrated significant, although incomplete inhibition of FAP enzymatic activity in the peripheral blood.Conclusion: This phase II trial of Val-boroPro demonstrated minimal clinical activity in patients with previously treated metastatic colorectal cancer. However it provides the initial proof-of-concept that physiologic inhibition of FAP activity can be accomplished in patients with colorectal cancer, and lays the groundwork for future studies targeting the tumor stroma.

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“…The active enzyme is a homodimer of two 97-kd subunits, and a soluble form of FAP␣ has also been reported (131,132). In contrast to DPP-4, FAP␣ typically is not expressed in normal tissues.…”

Section: )mentioning

confidence: 99%