title: Proteolytic activity of prostate-specific antigen (PSA) towards protein substrates and effect of peptides stimulating PSA activity.
abstract: Prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3) exerts chymotrypsin-like proteolytic activity. The main biological function of PSA is the liquefaction of the clot formed after ejaculation by cleavage of semenogelins I and II in seminal fluid. PSA also cleaves several other substrates, which may explain its putative functions in prostate cancer and its antiangiogenic activity. We compared the proteolytic efficiency of PSA towards several protein and peptide substrates and studied the effect of peptides stimulating the activity of PSA with these substrates. An endothelial cell tube formation model was used to analyze the effect of PSA-degraded protein fragments on angiogenesis. We showed that PSA degrades semenogelins I and II much more efficiently than other previously identified protein substrates, e.g., fibronectin, galectin-3 and IGFBP-3. We identified nidogen-1 as a new substrate for PSA. Peptides B2 and C4 that stimulate the activity of PSA towards small peptide substrates also enhanced the proteolytic activity of PSA towards protein substrates. Nidogen-1, galectin-3 or their fragments produced by PSA did not have any effect on endothelial cell tube formation. Although PSA cleaves several other protein substrates, in addition to semenogelins, the physiological importance of this activity remains speculative. The PSA levels in prostate are very high, but several other highly active proteases, such as hK2 and trypsin, are also expressed in the prostate and may cleave protein substrates that are weakly cleaved by PSA.
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Mattsson
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Ravela
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Can
authors.initials: C
authors.lastname: Hekim
authors.affiliation: Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University and Laboratory Medicine Skåne, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jonsson
authors.affiliation: Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University and Laboratory Medicine Skåne, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ale
authors.initials: A
authors.lastname: Närvänen
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Ulf-Håkan
authors.initials: UH
authors.lastname: Stenman
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
mesh_terms: D005353:Fibronectins; D037502:Galectin 3 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis
chemical_list: D005353:Fibronectins; D037502:Galectin 3; D018972:Insulin-Like Growth Factor Binding Protein 3; D008562:Membrane Glycoproteins; D010455:Peptides; C029967:nidogen; D017430:Prostate-Specific Antigen