Specific cleavage of insulin-like growth factor-binding protein-1 by a novel protease activity.
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.
Wang
J
J
Department of Molecular Medicine and Surgery, L1:01, Karolinska Institutet and Hospital Solna, 171 76, Stockholm, Sweden.
Shafqat
J
J
Hall
K
K
Ståhlberg
M
M
Wivall-Helleryd
I-L
IL
Bouzakri
K
K
Zierath
J R
JR
Brismar
K
K
Jörnvall
H
H
Lewitt
M S
MS
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
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