Pregnancy‐associated plasma protein‐A (PAPP‐A) cleaves insulin‐like growth factor binding protein (IGFBP)‐5 independent of IGF: implications for the mechanism of IGFBP‐4 proteolysis by PAPP‐A

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Abstract
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.

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