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PAPP-A and the IGF system

Philippe Monget1, Claus Oxvig2

  • 1Institut national de la recherche agronomique, physiologie de la reproduction et des comportements, 37380 Nouzilly, France.

Annales D'Endocrinologie
|May 9, 2016
PubMed

Insights

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that regulates insulin-like growth factor (IGF) bioavailability by cleaving IGF binding proteins. Targeting PAPP-A offers a strategy to modulate IGF signaling in various tissues.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase initially identified as a placental protein.
  • PAPP-A is widely expressed and cleaves insulin-like growth factor binding proteins (IGFBPs), specifically IGFBP-2, -4, and -5.
  • It functions locally as a growth-promoting enzyme by releasing bioactive IGF near its receptor.

Purpose of the Study:

  • To elucidate the mechanisms regulating PAPP-A activity and its role in IGF bioavailability.
  • To explore PAPP-A as a potential therapeutic target for modulating IGF signaling.

Main Methods:

  • Investigated PAPP-A's enzymatic activity and substrate specificity (IGFBP-2, -4, -5).
  • Examined PAPP-A's interaction with glycosaminoglycans and inhibitors like pro-MBP and stanniocalcin-2 (STC2).
  • Utilized in vivo experiments to assess the role of IGFBP-4 as a key PAPP-A substrate.

Main Results:

  • PAPP-A specifically cleaves IGFBP-2, -4, and -5, influencing IGF bioavailability.
  • Pro-MBP and STC2 inhibit PAPP-A activity through complex formation.
  • IGFBP-4 is identified as the primary substrate for PAPP-A in regulating IGF bioavailability.
  • Regulation mechanisms include transcriptional control, competition with other IGFBPs, and proteolytic inhibition.

Conclusions:

  • PAPP-A plays a crucial role in modulating IGF bioavailability through specific IGFBP cleavage.
  • The interaction between PAPP-A and IGFBP-4 is key for regulating IGF signaling.
  • PAPP-A represents a viable therapeutic target for inhibiting IGF signaling driven by elevated PAPP-A activity.

Keywords:
IGF, IGFBP, Protéine-A plasmatique (PAPP-A), Pappalysine, PAPP-A, Pro-MBP, StanniocalcineInsulin-like growth factor (IGF)Insulin-like growth factor binding protein (IGFBP)PappalysinPregnancy-associated plasma protein-A (PAPP-A)Proform of eosinophil major basic protein (pro-MBP)Stanniocalcin (STC)

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