Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand

Tracy Vargo-Gogola, Howard C. Crawford, Barbara Fingleton, Lynn M. Matrisian

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Soluble Fas ligand (sFasL) is released from the cell surface by matrix metalloproteinases (MMPs), one of which is MMP-7. We have reported that MMP-7-generated sFasL is pro-apoptotic in both in vitro and in vivo systems. However, there are contradictory reports that the soluble form of FasL is inactive or anti-apoptotic, resulting in significant controversy in the literature. One potential explanation for these discrepancies is that forms of sFasL with different amino-terminal sequences have been demonstrated to have varying activities. Here we report that MMP-7 cleaves murine and human FasL at sites that are distinct from previously reported cleavage sites resulting in production of novel forms of sFasL. Cleavage of FasL by MMP-7 occurs at the leucine residues in the sequence "ELAELR" within the region between the transmembrane and trimerization domains. When this site is unavailable, a more c-terminal site, "SL," is cleaved. MMP-7 di4erentially processes murine and human FasL since it cleaves human FasL not only at the "ELAELR" site but also at a previously identified site. Additionally, MMP-3, but not MMP-2, was found to have the same cleavage specificity for murine FasL as MMP-7. We conclude that the controversy regarding the biological activity of sFasL may be explained, in part, by the generation of distinct forms of sFasL as a result of cleavage at specific sequences.

Original languageEnglish (US)
Pages (from-to)155-161
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume408
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 7
Fas Ligand Protein
Matrix Metalloproteinase 3
Matrix Metalloproteinase 2
Bioactivity
Matrix Metalloproteinases
Leucine

Keywords

  • Apoptosis
  • MMP-3
  • MMP-7
  • Proteolysis
  • Soluble FasL

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. / Vargo-Gogola, Tracy; Crawford, Howard C.; Fingleton, Barbara; Matrisian, Lynn M.

In: Archives of Biochemistry and Biophysics, Vol. 408, No. 2, 2002, p. 155-161.

Research output: Contribution to journalArticle

@article{8dd3cb20e42e4148ab2e343a46c8ab32,
title = "Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand",
abstract = "Soluble Fas ligand (sFasL) is released from the cell surface by matrix metalloproteinases (MMPs), one of which is MMP-7. We have reported that MMP-7-generated sFasL is pro-apoptotic in both in vitro and in vivo systems. However, there are contradictory reports that the soluble form of FasL is inactive or anti-apoptotic, resulting in significant controversy in the literature. One potential explanation for these discrepancies is that forms of sFasL with different amino-terminal sequences have been demonstrated to have varying activities. Here we report that MMP-7 cleaves murine and human FasL at sites that are distinct from previously reported cleavage sites resulting in production of novel forms of sFasL. Cleavage of FasL by MMP-7 occurs at the leucine residues in the sequence {"}ELAELR{"} within the region between the transmembrane and trimerization domains. When this site is unavailable, a more c-terminal site, {"}SL,{"} is cleaved. MMP-7 di4erentially processes murine and human FasL since it cleaves human FasL not only at the {"}ELAELR{"} site but also at a previously identified site. Additionally, MMP-3, but not MMP-2, was found to have the same cleavage specificity for murine FasL as MMP-7. We conclude that the controversy regarding the biological activity of sFasL may be explained, in part, by the generation of distinct forms of sFasL as a result of cleavage at specific sequences.",
keywords = "Apoptosis, MMP-3, MMP-7, Proteolysis, Soluble FasL",
author = "Tracy Vargo-Gogola and Crawford, {Howard C.} and Barbara Fingleton and Matrisian, {Lynn M.}",
year = "2002",
doi = "10.1016/S0003-9861(02)00525-8",
language = "English (US)",
volume = "408",
pages = "155--161",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand

AU - Vargo-Gogola, Tracy

AU - Crawford, Howard C.

AU - Fingleton, Barbara

AU - Matrisian, Lynn M.

PY - 2002

Y1 - 2002

N2 - Soluble Fas ligand (sFasL) is released from the cell surface by matrix metalloproteinases (MMPs), one of which is MMP-7. We have reported that MMP-7-generated sFasL is pro-apoptotic in both in vitro and in vivo systems. However, there are contradictory reports that the soluble form of FasL is inactive or anti-apoptotic, resulting in significant controversy in the literature. One potential explanation for these discrepancies is that forms of sFasL with different amino-terminal sequences have been demonstrated to have varying activities. Here we report that MMP-7 cleaves murine and human FasL at sites that are distinct from previously reported cleavage sites resulting in production of novel forms of sFasL. Cleavage of FasL by MMP-7 occurs at the leucine residues in the sequence "ELAELR" within the region between the transmembrane and trimerization domains. When this site is unavailable, a more c-terminal site, "SL," is cleaved. MMP-7 di4erentially processes murine and human FasL since it cleaves human FasL not only at the "ELAELR" site but also at a previously identified site. Additionally, MMP-3, but not MMP-2, was found to have the same cleavage specificity for murine FasL as MMP-7. We conclude that the controversy regarding the biological activity of sFasL may be explained, in part, by the generation of distinct forms of sFasL as a result of cleavage at specific sequences.

AB - Soluble Fas ligand (sFasL) is released from the cell surface by matrix metalloproteinases (MMPs), one of which is MMP-7. We have reported that MMP-7-generated sFasL is pro-apoptotic in both in vitro and in vivo systems. However, there are contradictory reports that the soluble form of FasL is inactive or anti-apoptotic, resulting in significant controversy in the literature. One potential explanation for these discrepancies is that forms of sFasL with different amino-terminal sequences have been demonstrated to have varying activities. Here we report that MMP-7 cleaves murine and human FasL at sites that are distinct from previously reported cleavage sites resulting in production of novel forms of sFasL. Cleavage of FasL by MMP-7 occurs at the leucine residues in the sequence "ELAELR" within the region between the transmembrane and trimerization domains. When this site is unavailable, a more c-terminal site, "SL," is cleaved. MMP-7 di4erentially processes murine and human FasL since it cleaves human FasL not only at the "ELAELR" site but also at a previously identified site. Additionally, MMP-3, but not MMP-2, was found to have the same cleavage specificity for murine FasL as MMP-7. We conclude that the controversy regarding the biological activity of sFasL may be explained, in part, by the generation of distinct forms of sFasL as a result of cleavage at specific sequences.

KW - Apoptosis

KW - MMP-3

KW - MMP-7

KW - Proteolysis

KW - Soluble FasL

UR - http://www.scopus.com/inward/record.url?scp=0036910998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036910998&partnerID=8YFLogxK

U2 - 10.1016/S0003-9861(02)00525-8

DO - 10.1016/S0003-9861(02)00525-8

M3 - Article

C2 - 12464266

AN - SCOPUS:0036910998

VL - 408

SP - 155

EP - 161

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 2

ER -