title: Specific cleavage of insulin-like growth factor-binding protein-1 by a novel protease activity.
abstract: Insulin-like growth factor-binding protein-1 (IGFBP-1) is secreted in a highly phosphorylated form that binds IGF-I with high affinity and is resistant to proteolysis. We have purified IGFBP-1-specific protease activity from the urine of an individual with multiple myeloma. This protease efficiently cleaves both phosphorylated and non-phosphorylated IGFBP-1 at Ile130-Ser131, generating fragments that together have higher association and dissociation rates for IGFs compared with intact IGFBP-1. The proteolytic fraction contained azurocidin, a protease homologue hitherto considered inactive. After cleavage of IGFBP-1, there was a lower affinity, but higher capacity for IGF-I binding, suggesting both N- and C-terminal fragments may interact with ligand independently. There was decreased inhibition of IGF-II-stimulated cell growth and glucose uptake. Alone, proteolysed IGFBP-1 stimulated glucose uptake in muscle. We conclude that specific cleavage of IGFBP-1 at target tissues is important in cellular growth and metabolism and opens novel strategies for targeting IGFBP-1 in treatment of disease.
authors.affiliation: Department of Molecular Medicine and Surgery, L1:01, Karolinska Institutet and Hospital Solna, 171 76, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Shafqat
authors.forename: K
authors.initials: K
authors.lastname: Hall
authors.forename: M
authors.initials: M
authors.lastname: Ståhlberg
authors.forename: I-L
authors.initials: IL
authors.lastname: Wivall-Helleryd
authors.forename: K
authors.initials: K
authors.lastname: Bouzakri
authors.forename: J R
authors.initials: JR
authors.lastname: Zierath
authors.forename: K
authors.initials: K
authors.lastname: Brismar
authors.forename: H
authors.initials: H
authors.lastname: Jörnvall
authors.forename: M S
authors.initials: MS
authors.lastname: Lewitt
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D001665:Binding Sites; D001798:Blood Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D002352:Carrier Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism
chemical_list: C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D020033:Protein Isoforms; D013002:Somatomedins; D010447:Peptide Hydrolases