TY - JOUR
T1 - Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF
T2 - Implications for the mechanism of IGFBP-4 proteolysis by PAPP-A
AU - Laursen, Lisbeth S.
AU - Overgaard, Michael T.
AU - Soe, Rikke
AU - Boldt, Henning B.
AU - Sottrup-Jensen, Lars
AU - Giudice, Linda C.
AU - Conover, Cheryl A.
AU - Oxvig, Claus
N1 - Funding Information:
This work was supported by grants (to C.O.) from the Danish Medical Research Council, the Novo Nordic Foundation, and from the Alfred Benzon Foundation, and by a Grant (HD31579-07 to L.C.G., C.O., C.A.C.) from the National Institute of Health.
PY - 2001/8/24
Y1 - 2001/8/24
N2 - Pregnancy-associated plasma protein-A (PAPP-A) has recently been identified as the proteinase responsible for cleavage of insulin-like growth factor binding protein (IGFBP)-4, an inhibitor of IGF action, in several biological fluids. Cleavage of IGFBP-4 by PAPP-A is believed to occur only in the presence of IGF. We here report that in addition to IGFBP-4, PAPP-A also cleaves IGFBP-5. Cleavage occurs at one site, between Ser-143 and Lys-144 of IGFBP-5. In the presence of IGF, IGFBP-4 and -5 are cleaved with similar rates by PAPP-A. Interestingly, cleavage of IGFBP-5 by PAPP-A does not require the presence of IGF, but is slightly inhibited by IGF. These findings have implications for the mechanism of proteolysis of IGFBP-4 by PAPP-A, suggesting that IGFBP-4 binds IGF, which then becomes a PAPP-A substrate. Using highly purified, recombinant proteins, we establish that (1) PAPP-A cleavage of IGFBP-4 can occur in the absence of IGF, although the rate of hydrolysis is very slow, and (2) IGF is unable to bind to PAPP-A. We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out.
AB - Pregnancy-associated plasma protein-A (PAPP-A) has recently been identified as the proteinase responsible for cleavage of insulin-like growth factor binding protein (IGFBP)-4, an inhibitor of IGF action, in several biological fluids. Cleavage of IGFBP-4 by PAPP-A is believed to occur only in the presence of IGF. We here report that in addition to IGFBP-4, PAPP-A also cleaves IGFBP-5. Cleavage occurs at one site, between Ser-143 and Lys-144 of IGFBP-5. In the presence of IGF, IGFBP-4 and -5 are cleaved with similar rates by PAPP-A. Interestingly, cleavage of IGFBP-5 by PAPP-A does not require the presence of IGF, but is slightly inhibited by IGF. These findings have implications for the mechanism of proteolysis of IGFBP-4 by PAPP-A, suggesting that IGFBP-4 binds IGF, which then becomes a PAPP-A substrate. Using highly purified, recombinant proteins, we establish that (1) PAPP-A cleavage of IGFBP-4 can occur in the absence of IGF, although the rate of hydrolysis is very slow, and (2) IGF is unable to bind to PAPP-A. We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out.
KW - Insulin-like growth factor
KW - Insulin-like growth factor binding protein-4
KW - Insulin-like growth factor binding protein-5
KW - Pregnancy-associated plasma protein-A
KW - Proteolysis
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U2 - 10.1016/S0014-5793(01)02760-0
DO - 10.1016/S0014-5793(01)02760-0
M3 - Article
C2 - 11522292
AN - SCOPUS:0035943504
SN - 0014-5793
VL - 504
SP - 36
EP - 40
JO - FEBS Letters
JF - FEBS Letters
IS - 1-2
ER -