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Pappalysin-2 (PAPPA2)
- Target
- PAPPA2
- Molecular classification
- Enzyme, Metalloproteinase, Metzincin metalloproteinase, Pappalysin family
01
Overview
Pappalysin-2 (PAPPA2) is a secreted, glycosylated member of the pappalysin-metzincin metalloproteinase family that specifically cleaves IGFBP-5 (and to a lesser degree IGFBP-3), enhancing local IGF bioavailability. PAPPA2 is highly expressed in placental tissues, especially syncytiotrophoblasts, and is upregulated under pathological conditions such as preeclampsia, where it may represent a compensatory response to impaired trophoblast invasion or hypoxia. Loss-of-function mutations lead to syndromes involving postnatal growth failure, abnormal IGF/IGFBP levels, and bone mineral density reduction, highlighting its role in the growth hormone/IGF axis. Circulating PAPPA2 levels and genetic variants are relevant in cardiovascular, metabolic, and skeletal disorders, making PAPPA2 a promising biomarker and potential therapeutic target.
- Other names
- Pregnancy-associated plasma protein A2PAPP-A2PAPP-EPLAC3Papalysin-2PAPPESSDAPlacenta-specific 3Pregnancy-associated plasma protein E1Pregnancy-associated plasma preproprotein-A2
02
Mechanism of action
Inhibition by endogenous proteins such as stanniocalcin-1 (STC1) and stanniocalcin-2 (STC2), which reduce PAPPA2 activity through covalent complex formation
03
Biological functions
Cleavage of insulin-like growth factor binding proteins (primarily IGFBP-5 and IGFBP-3)Regulation of IGF bioavailabilityModulation of growth hormone/IGF axisLocal regulation of growth and development (especially placental and fetal)Regulation of trophoblast migration and invasionInvolvement in bone remodeling and turnover
04
Disease associations
Growth disorders (postnatal growth failure, microcephaly, reduced bone mineral density)Preeclampsia and placental insufficiencyCardiovascular disorders (especially salt-sensitive hypertension)Developmental dysplasia of the hip and potentially early osteoarthritisPotential biomarker for prenatal screening and prediction of preeclampsia complications
05
Safety considerations
Notable therapeutic challenges include off-target effects on systemic IGF signalingManipulation of PAPPA2 activity may alter fetal development, placental function, and bone remodeling, leading to systemic risks
06
Interacting drugs
None directly approved or commonly referenced as interacting with PAPPA2; research into inhibitors (such as stanniocalcins) is ongoing
07
Biomarkers
Circulating PAPPA2 levels are used as a biomarker in prenatal screening (especially for preeclampsia)Genetic variants in PAPPA2 may predict growth disorders and cardiovascular risks
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