Affinage

PAPPA

Pappalysin-1 · UniProt Q13219

Length
1627 aa
Mass
181.0 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAPP-A (pappalysin-1) is a cell surface-associated metzincin metalloproteinase that locally amplifies insulin-like growth factor (IGF) signaling by cleaving inhibitory IGF binding proteins in an IGF-dependent manner, principally IGFBP-4 but also IGFBP-2 and IGFBP-5, thereby liberating bioactive IGF for IGF receptor activation in the pericellular space (PMID:17218136, PMID:25617049). Tight binding to cell-surface glycosaminoglycans positions PAPP-A to act locally on its substrates (PMID:17218136, PMID:25617049). Structural work resolved how substrate engagement and inhibition occur: PAPP-A is a flexible trans-dimer whose central domain mediates both IGFBP recognition and trans-dimerization, with IGFBP5 captured via a 25-residue anchor peptide reaching into the active site; trans-dimer formation is required for efficient IGFBP-4 but not IGFBP-5 proteolysis (PMID:36127359). Its proteolytic activity is endogenously suppressed by stanniocalcin-2 through a covalent 2:2 complex in which STC2 forms an intermolecular disulfide and sterically excludes IGFBP-4 from the substrate-binding region while leaving the catalytic site accessible to peptides (PMID:36257932). Through this IGF-releasing activity PAPP-A acts as a local effector across tissues: it is required for ovarian steroidogenesis and female fertility (PMID:20130263), maternal adipose remodeling in pregnancy (PMID:33239385), and drives pathology in diabetic nephropathy, polycystic kidney disease, and multiple cancers via IGF-1R/PI3K/Akt signaling (PMID:31990681, PMID:22503545, PMID:26336825). Inhibitory monoclonal antibodies targeting the IGFBP-4-cleavage exosite suppress AKT signaling and tumor growth, establishing the proteolytic function as therapeutically tractable (PMID:24572990, PMID:31990681). PAPP-A transcription is induced by inflammatory cytokines via NF-κB, repressed by PPARγ, and activated by cAMP/CREB and by sirtuin-deficiency-driven chromatin rewiring linked to senescence (PMID:22997483, PMID:16388849, PMID:31990681, PMID:38484732). Beyond its protease function, PAPP-A also possesses at least one IGF-independent biological activity, demonstrated in zebrafish where a catalytically dead protein rescues a developmental phenotype (PMID:23430244).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1979 Medium

    Before any enzymatic role was known, the first question was simply what kind of protein PAPP-A is; early purification defined it as a large, acidic glycoprotein and tentatively assigned in vitro effects on coagulation and complement.

    Evidence Protein purification and in vitro complement/plasmin/coagulation inhibition assays

    PMID:518134

    Open questions at the time
    • The coagulation/complement activities were not corroborated by later mechanistic work
    • No catalytic or substrate identity established at this stage
  2. 1983 Medium

    Refining the early biochemical picture, the anticoagulant effect was shown to act indirectly via antithrombin III activation and to depend on strongly acidic (heparin-like) residues, hinting at the charged surface properties later relevant to glycosaminoglycan binding.

    Evidence In vitro coagulation assay with antithrombin III titration and protamine sulfate neutralization

    PMID:6197764

    Open questions at the time
    • Physiological relevance of anticoagulant activity unestablished
    • No connection to a catalytic mechanism
  3. 1993 High

    Genomic localization was needed to enable molecular study; FISH mapped PAPPA to 9q33.1.

    Evidence Fluorescence in situ hybridization on mitotic and meiotic chromosomes

    PMID:7679961

    Open questions at the time
    • Mapping alone provides no functional information
  4. 1999 High

    The defining mechanistic breakthrough resolved what PAPP-A actually does: it is the long-sought IGF-dependent IGFBP-4 protease, cleaving IGFBP-4 only when IGF is bound and thereby releasing bioactive IGF.

    Evidence Biochemical purification and protease activity assay from human fibroblast conditioned media

    PMID:17218136

    Open questions at the time
    • Did not define catalytic mechanism or structural basis of IGF dependence
    • Full substrate repertoire not yet established
  5. 2007 High

    Synthesizing across studies established PAPP-A as a metzincin metalloproteinase that cleaves IGFBP-4/-2/-5 and binds cell-surface glycosaminoglycans, positioning it as a local amplifier of pericellular IGF signaling.

    Evidence Review integrating biochemical assays, cell-surface binding experiments, and knockout mouse data

    PMID:17218136 PMID:25617049

    Open questions at the time
    • Structural basis of cell-surface tethering not resolved
    • How catalysis is regulated in vivo unclear
  6. 2010 High

    To test physiological necessity of the protease activity, knockout mice showed loss of ovarian IGFBP-4 proteolysis causes reduced ovulation, lowered steroid hormones, and impaired fertility, establishing an in vivo reproductive role.

    Evidence Pappa knockout mouse with follicular IGFBP-4 activity assay, serum hormone, and ovarian gene expression

    PMID:20130263

    Open questions at the time
    • Did not separate proteolytic from non-proteolytic contributions
    • Upstream regulation of ovarian PAPP-A not addressed
  7. 2013 High

    A pivotal question was whether PAPP-A function is solely proteolytic; rescue of a zebrafish developmental phenotype by catalytically dead protein demonstrated a biologically important IGF-independent, non-proteolytic function.

    Evidence Zebrafish morpholino knockdown rescued by wild-type vs. active-site-mutant papp-a mRNA

    PMID:23430244

    Open questions at the time
    • Molecular identity of the non-proteolytic function unknown
    • No partner or pathway for this activity identified
  8. 2014 High

    To establish therapeutic tractability and confirm that IGFBP-4 cleavage drives pericellular IGF signaling, an exosite-targeting inhibitory antibody suppressed AKT signaling and tumor growth.

    Evidence Inhibitory mAb (Ki=135 pM), AKT phosphorylation assay, and A549 xenograft model

    PMID:24572990

    Open questions at the time
    • Tested in a single tumor model
    • Did not address resistance or systemic effects
  9. 2022 High

    The structural basis of endogenous inhibition and substrate recognition was resolved: STC2 inhibits PAPP-A by covalent disulfide locking and steric substrate exclusion, while a separate structure showed PAPP-A as a trans-dimer engaging IGFBP via an anchor peptide reaching the active site.

    Evidence Single-particle cryo-EM of the 2:2 PAPP-A·STC2 complex and of inactive PAPP-A(E483A) with an IGFBP5 peptide, plus mutagenesis and cleavage assays

    PMID:36127359 PMID:36257932

    Open questions at the time
    • Structures cover N-terminal/central regions; full-length conformational dynamics incomplete
    • Structural basis of cell-surface and glycosaminoglycan binding not resolved
  10. 2020 High

    Recurring questions about tissue-specific roles were addressed by knockout and antibody studies showing PAPP-A drives cyst growth in polycystic kidney disease, maternal adipose remodeling, and depot-selective visceral adiposity through IGF bioavailability.

    Evidence Pappa KO and anti-PAPP-A mAb in Pkd1 and high-fat-diet mouse models, ex vivo human adipose assays with pathway-specific neutralization

    PMID:31990681 PMID:32888014 PMID:33239385

    Open questions at the time
    • Mechanism of depot selectivity not fully resolved
    • Whether non-proteolytic function contributes to these phenotypes untested
  11. 2019 High

    In cancer, CRISPR and antibody studies established PAPP-A as essential for tumor cell survival and metastasis, acting via local IGF-1 bioavailability and, in mammary metastasis, the collagen receptor DDR2.

    Evidence CRISPR knockout, RNA-seq, and xenograft in Ewing sarcoma; DDR2 CRISPR epistasis and collagen imaging in mammary models

    PMID:30698726 PMID:31046834

    Open questions at the time
    • Link between PAPP-A protease activity and DDR2 activation not mechanistically resolved
    • Interferon/immune-evasion connection in EWS correlative
  12. 2024 Medium

    Transcriptional control of PAPPA was progressively mapped to inflammatory cytokine/NF-κB and JNK/p38 signaling, PPARγ repression, cAMP/CREB activation, and sirtuin-deficiency-driven chromatin rewiring that converges on PAPPA to mediate senescence.

    Evidence Cytokine and pathway-inhibitor studies in PBMCs, mesangial cells, and preadipocytes; PPARγ agonist in trophoblasts; Hi-C/ChIP-seq with PAPPA knockdown in sirtuin-KO stem cells

    PMID:16388849 PMID:22997483 PMID:24781252 PMID:27519211 PMID:38484732

    Open questions at the time
    • Direct PAPPA promoter/enhancer elements not fully defined
    • Integration of these regulatory inputs in vivo unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity and partners of the IGF-independent, non-proteolytic PAPP-A function remain undefined.
  • No effector or pathway identified for the non-proteolytic activity
  • Whether it operates in mammalian tissues is untested
  • No structural correlate of a non-catalytic function

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 3
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4
Partners
DDR2IGF1IGFBP2IGFBP4IGFBP5STC2
Complex memberships
PAPP-A trans-dimerPAPP-A·STC2 2:2 inhibitory complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PAPP-A was identified as the IGF-dependent IGFBP-4 protease activity present in conditioned media from human fibroblasts; it cleaves IGFBP-4 only when IGF is bound to IGFBP-4, releasing bioactive IGF. Biochemical purification and protease activity assay from human fibroblast conditioned media Growth hormone & IGF research High 17218136
1979 PAPP-A was purified and characterized as an alpha-2 glycoprotein of ~750–820 kDa, likely a dimer composed of two polypeptide chains of ~218 kDa each; in vitro it inhibited complement activity, caseinolytic activity of plasmin, and thrombin-induced coagulation via activation of antithrombin III. Protein purification (ammonium sulfate precipitation, ion-exchange, affinity chromatography, gel filtration); in vitro complement, plasmin, and coagulation inhibition assays Archives of gynecology Medium 518134
1983 Purified PAPP-A inhibits thrombin-induced coagulation of plasma by activating endogenous antithrombin III (not by direct inhibition of thrombin); this inhibitory effect is neutralized by protamine sulfate, suggesting PAPP-A carries strongly acidic (heparin-like) residues. In vitro coagulation assay with purified PAPP-A, euglobulin system, antithrombin III titration, protamine sulfate neutralization Thrombosis research Medium 6197764
2007 PAPP-A is a metzincin metalloproteinase that cleaves IGFBP-4 (and IGFBP-2 and IGFBP-5) in an IGF-dependent manner; it is cell surface-associated via tight binding to glycosaminoglycans, positioning it to increase local IGF bioavailability for IGF receptor activation. Review of biochemical assays, cell-surface binding experiments, and PAPP-A knockout mouse studies Growth hormone & IGF research High 17218136 25617049
2010 PAPP-A knockout (KO) female mice show complete loss of ovarian IGFBP-4 proteolytic activity, reduced ovulated oocyte numbers, lower estradiol and progesterone levels, and reduced steroidogenic enzyme gene expression, demonstrating that PAPP-A-mediated IGFBP-4 cleavage is required for normal ovarian steroidogenesis and female fertility. Pappa gene-targeted knockout mouse; IGFBP-4 proteolytic activity assay in follicular fluid; serum hormone measurement; ovarian gene expression analysis Biology of reproduction High 20130263
2014 An inhibitory monoclonal antibody (mAb 1/41) targeting a substrate-binding exosite of PAPP-A selectively inhibits IGFBP-4 cleavage (Ki = 135 pM), suppresses IGF receptor (AKT) signaling in lung cancer cells, and inhibits tumor growth in a murine A549 xenograft model, establishing that PAPP-A's proteolytic activity toward IGFBP-4 is required for pericellular IGF signaling. Inhibitory monoclonal antibody development; in vitro IGFBP-4 cleavage assay; AKT phosphorylation assay in cell monolayers; murine xenograft tumor model; tumor tissue immunohistochemistry Oncotarget High 24572990
2022 Cryo-EM structure of the 500 kDa 2:2 PAPP-A·stanniocalcin-2 (STC2) complex (3.1 Å for the STC2 and N-terminal ~1000 residues of PAPP-A) revealed that STC2 inhibits PAPP-A via: (1) a specific intermolecular disulfide bond preventing dissociation, and (2) interactions between STC2 and the very C-terminal module of PAPP-A that sterically prevent IGFBP-4 binding; the catalytic active site remains accessible to synthetic peptides, establishing an unusual substrate-exclusion mechanism of inhibition. Single-particle cryo-electron microscopy (cryo-EM); synthetic peptide hydrolysis assay; biochemical characterization of PAPP-A·STC2 complex Nature communications High 36257932
2022 Cryo-EM structures of catalytically inactive PAPP-A(E483A) alone and in complex with an IGFBP5 peptide revealed that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a unique 25-amino acid anchor peptide extending into the metalloprotease active site; the central domain of PAPP-A mediates both IGFBP5 recognition and trans-dimerization; trans-dimer formation and distal inter-domain interactions are required for efficient proteolysis of IGFBP4 but dispensable for IGFBP5 cleavage. Single-particle cryo-EM; AlphaFold-assisted model building; active-site mutant (E483A); biochemical proteolysis assays with IGFBP4 and IGFBP5 Nature communications High 36127359
2013 In zebrafish, knockdown of papp-a slows developmental rate beginning at gastrulation; this phenotype is rescued by proteolytically inactive Papp-a mRNA as efficiently as wild-type, demonstrating that Papp-a has a biologically important function independent of its IGFBP proteolytic activity. Zebrafish morpholino knockdown; rescue with wild-type vs. proteolytically inactive (active-site mutant) Papp-a mRNA; in vitro recombinant proteolytic activity assay The Journal of biological chemistry High 23430244
2019 PAPP-A is expressed on the cell surface of Ewing sarcoma (EWS) cells; CRISPR/Cas9 knockout of PAPPA revealed an essential survival role through local IGF-1 bioavailability regulation; PAPPA knockout also induced interferon-response genes involved in antigen processing/presentation, linking PAPP-A to immune evasion in EWS. CRISPR/Cas9 knockout; anti-PAPP-A antibody treatment; NSG xenograft orthotopic tumor model; RNA-sequencing on PAPPA-KO vs. control EWS clones Journal of the National Cancer Institute High 30698726
2020 PAPPA regulates maternal adipose tissue remodeling in pregnancy through IGF bioavailability; recombinant PAPPA stimulates ex vivo human adipose tissue expansion in an IGFBP-5- and IGF-1-dependent manner; Pappa-KO mice show impaired adipose remodeling, pregnancy-induced insulin resistance, and hepatic steatosis, phenocopying aspects of gestational diabetes. Pappa knockout mouse model; ex vivo human adipose tissue expansion assay with recombinant PAPPA; IGFBP-5 and IGF-1R neutralization to confirm pathway dependence; clinical cohort correlation Science translational medicine High 33239385
2020 PAPP-A transcription in polycystic kidney disease (ADPKD) is regulated through the cAMP/CREB/CBP/p300 pathway; PAPP-A deficiency inhibits cyst development in Pkd1RC/RC mice; treatment with an anti-PAPP-A monoclonal antibody blocking IGFBP4 proteolysis ameliorates cystic disease in vivo and ex vivo in embryonic kidneys, establishing PAPP-A/IGF-1 signaling as a driver of cyst growth. Pappa knockout in Pkd1RC/RC mouse model; cAMP/CREB pathway inhibitor experiments; monoclonal antibody treatment (mAb targeting IGFBP4-proteolysis exosite) in vivo and in embryonic kidney cultures; histopathology JCI insight High 31990681
2012 PAPP-A decreases expression of ABCA1, ABCG1, and SR-B1 and reduces cholesterol efflux in THP-1 macrophage-derived foam cells by activating the IGF-1/PI3K/Akt signaling pathway, which downregulates LXRα; PI3K inhibitors or IGF-1R siRNA (but not MAPK inhibitors) rescued the effect. PAPP-A protein treatment of THP-1 macrophage-derived foam cells; PI3K inhibitors; IGF-1R siRNA knockdown; LXRα agonist rescue experiment; RT-PCR and Western blot for ABCA1/ABCG1/SR-B1/LXRα; cholesterol efflux assay Atherosclerosis Medium 22503545
2003 PAPP-A expression and secretion are strongly upregulated during in vitro differentiation of villous cytotrophoblasts into syncytiotrophoblasts (~19-fold increase in mRNA, ~8-fold increase in secretion), independent of gestational age. Primary human villous cytotrophoblast culture; real-time PCR; immunocytochemistry; TRACE immunoassay for secreted PAPP-A Placenta Medium 12744930
2006 PPARγ activation inhibits PAPP-A gene expression and secretion in invasive extravillous cytotrophoblasts (EVCT) but not in villous cytotrophoblasts (VCT); since PPARγ agonist inhibits EVCT invasion, PPARγ-mediated downregulation of PAPP-A may reduce bioactive IGF-II and thereby decrease trophoblast invasion. Primary EVCT and VCT cultures isolated from first-trimester chorionic villi; PPARγ agonist treatment; PAPP-A gene expression (RT-PCR) and secretion assay Placenta Medium 16388849
2013 PAPP-A-deficient mice show resistance to indicators of diabetic nephropathy (Bowman's capsule thickening, increased glomerular size, mesangial expansion, macrophage infiltration) despite equivalent hyperglycemia compared with wild-type diabetic mice, establishing a pathogenic role of PAPP-A in diabetic kidney disease. Pappa KO mouse; streptozotocin-induced diabetes; renal histopathology; immunohistochemistry for macrophage markers The Journal of endocrinology Medium 23881937
2016 In PAPP-A KO mice, mTORC1 activity is diminished and MGMT and NDRG1 (DNA repair proteins) are upregulated via post-transcriptional mechanisms; this upregulation is linked to alterations in the CCR4-NOT complex downstream of mTORC1, connecting PAPP-A deficiency to enhanced DNA damage repair and longevity. PAPP-A KO mouse; mTORC1 activity assay; Western blot for MGMT and NDRG1; CCR4-NOT complex analysis; post-transcriptional regulation assays Aging cell Medium 27618784
2019 The common SNP rs7020782 (serine variant) in PAPPA encodes a PAPP-A protein with significantly reduced proteolytic cleavage of IGFBP-4 compared to the tyrosine variant; no differences were found in cell-surface binding, complex formation with STC2 or proMBP, or STC1 inhibition, localizing the functional impact to IGFBP-4 proteolytic activity specifically. Recombinant PAPP-A variants expressed in HEK293T cells; IGFBP-4, IGFBP-2, IGFBP-5 cleavage assays; cell-surface binding assay; co-immunoprecipitation with STC2 and proMBP Scientific reports Medium 31519945
2021 PAPP-A inhibition (neutralizing antibody) reduces IGF signaling and ECM gene expression system-wide in adult mice; mesenchymal stromal cells (MSCs) in bone marrow are identified as the primary source of PAPP-A and the primary responders, with reduced MSC number and IGF signaling accounting for decreased bone, marrow adiposity, and myelopoiesis; MSC-like cells are also the major PAPP-A source in other tissues. PAPP-A neutralizing antibody treatment in adult mice; transcriptomic profiling across tissues; bone marrow fractionation; immunohistochemistry; IGF signaling assays Aging cell Medium 33561324
2019 PAPP-A activates the collagen receptor DDR2 and promotes metastasis in post-partum mammary glands; CRISPR deletion of DDR2 abolished the pro-invasive effect of PAPP-A, establishing DDR2 as a required downstream effector; PAPP-A also converts anti-proliferative post-partum collagen into pro-tumorigenic collagen architecture. PAPP-A transgenic/KO mouse model; second-harmonic generation microscopy for collagen architecture; CRISPR/Cas9 DDR2 knockout; invasion assay; transcriptomic analysis Breast cancer research Medium 31046834
2022 In human lung fibroblasts (NHLF), TGF-β treatment increases PAPP-A levels and proteolytic activity in conditioned medium ~4-fold and stimulates IGF-I expression; the resulting PI3K/Akt signaling is significantly inhibited by both IGF-I-inactivating and PAPP-A inhibitory antibodies; senescent NHLF secrete 10-fold more PAPP-A with increased proteolytic activity, and active PAPP-A is also present on secreted extracellular vesicles. Primary NHLF cultures; TGF-β treatment; PAPP-A activity assay; PI3K/Akt phosphorylation assay; IGF-I and PAPP-A inhibitory antibodies; senescence induction; extracellular vesicle isolation and characterization Journal of cellular physiology Medium 35098542
2015 In human ovarian carcinoma ascites, PAPP-A (present at 46-fold higher concentration than in serum) is predominantly enzymatically active and drives IGFBP-4 cleavage; ascites has greater IGF-IR-activating potency than serum, and addition of recombinant PAPP-A to ascites further increased IGFBP-4 cleavage and IGF-IR activation, establishing PAPP-A proteolytic activity as the mechanism enhancing IGF bioactivity in ovarian cancer. IGFBP-4 cleavage assay in ascites; IGF-IR activation bioassay; immunohistochemistry on tumor tissue; addition of recombinant PAPP-A ex vivo Oncotarget Medium 26336825
2016 Human adipose tissue cultures secrete enzymatically active PAPP-A in a depot-specific manner: visceral adipose tissue (VAT) secretes ~4-fold more PAPP-A and generates more PAPP-A-cleaved IGFBP-4 fragments than subcutaneous adipose tissue (SAT), with correspondingly greater IGF-IR-activating potency in VAT conditioned medium. Human adipose tissue explant cultures (VAT and SAT); PAPP-A ELISA; intact and cleaved IGFBP-4 fragment immunoassays; IGF-IR activation bioassay European journal of endocrinology Medium 27585595
2016 In human mesangial cells, IL-1β is the most potent stimulator of PAPP-A expression (~5-fold) followed by TNF-α (~2.5-fold); PAPP-A produced is secreted, cell-associated, and proteolytically active; IGF-1 complexed to wild-type but not protease-resistant IGFBP-4 stimulates mesangial cell proliferation, establishing that PAPP-A-mediated IGFBP-4 cleavage is required to release IGF-1 for mitogenic signaling in these cells. Primary human mesangial cell cultures; cytokine treatment; PAPP-A ELISA and activity assay; [3H]-thymidine incorporation proliferation assay with wild-type vs. protease-resistant IGFBP-4 The Journal of endocrinology Medium 27519211
2012 CRP and TNF-α induce PAPP-A mRNA and protein expression in human peripheral blood mononuclear cells (PBMCs) in a dose- and time-dependent manner; this induction is mediated through the NF-κB pathway, as demonstrated by actinomycin D and NF-κB inhibitor (BAY11-7082) experiments. Human PBMC cultures; CRP and TNF-α stimulation; RT-PCR, Western blot, ELISA; actinomycin D (transcription inhibitor); NF-κB inhibitor BAY11-7082 Mediators of inflammation Medium 22997483
2014 PAPP-A expression in human primary omental preadipocytes is preferentially elevated compared to mesenteric and subcutaneous preadipocytes; TNF-α and IL-1β upregulate PAPP-A expression via the NF-κB and JNK/p38 MAPK pathways; resveratrol downregulates PAPP-A expression under basal and stimulated conditions through SIRT1/AMPK-independent pathways. Primary human preadipocyte cultures from omental, mesenteric, and subcutaneous depots; cytokine treatment; pathway inhibitors; resveratrol treatment; qRT-PCR and protein assays The Journal of endocrinology Medium 24781252
2010 Heparin induces release of PAPP-A from normal arterial wall tissue (but not from non-arterial tissue or from atherosclerotic vulnerable plaques), suggesting that elevated circulating PAPP-A in acute coronary syndrome patients is due to heparin-mediated detachment from the arterial wall rather than secretion from vulnerable plaques. Immunohistochemistry on vulnerable plaques and control tissues; ex vivo heparin incubation of arterial vs. non-arterial tissue; PAPP-A measurement in volunteers receiving heparin Clinical biochemistry Medium 21185276
2020 Genetic or pharmacological (mAb-PA 1/41) inhibition of PAPP-A selectively reduces adipocyte size in visceral adipose tissue (VAT: mesenteric and pericardial) but not in subcutaneous adipose tissue (SAT) in mice on high-fat diet; in mesenteric fat, PAPP-A inhibition increased cell number (hyperplasia) alongside reduced hypertrophy, decreased macrophage marker (F4/80) and IL-6 expression, and increased adiponectin. Conditional PAPP-A gene knockdown in adult mice; anti-PAPP-A immunoneutralizing mAb (mAb-PA 1/41) in vivo; histology and adipocyte sizing; gene expression analysis Endocrinology High 32888014
2024 Sirtuin deficiency (any of SIRT1–SIRT7) drives chromatin rewiring via altered topologically associated domain (TAD) interactions and de novo enhancer-promoter loop formation, converging on aberrant transcriptional activation of the PAPPA gene; PAPPA mediates the pro-senescence effects downstream of sirtuin deficiency in human stem cells. Isogeneic human stem cell lines with SIRT1–SIRT7 knockouts; large-scale epigenomic analyses (Hi-C, ChIP-seq); 3D chromatin contact mapping; PAPPA knockdown in sirtuin-deficient cells; cellular senescence assays Developmental cell Medium 38484732
1993 The PAPPA gene was mapped to chromosomal region 9q33.1 by fluorescence in situ hybridization (FISH) using a 3.7-kb partial PAPPA cDNA probe on both mitotic and meiotic chromosomes. Fluorescence in situ hybridization (FISH) on mitotic and meiotic chromosomes Cytogenetics and cell genetics High 7679961

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The role of PAPP-A in the IGF system: location, location, location. Journal of cell communication and signaling 153 25617049
2007 Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 153 17218136
2002 Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenatal diagnosis 142 12224070
2008 Low levels of maternal serum PAPP-A in the first trimester and the risk of pre-eclampsia. Prenatal diagnosis 140 18000943
2017 Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. Prenatal diagnosis 87 28012202
1979 Purification and characterization of pregnancy associated plasma protein A (PAPP-A). Archives of gynecology 78 518134
2012 PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway. Atherosclerosis 69 22503545
2000 Maternal serum free beta-hCG and PAPP-A in fetal sex chromosome defects in the first trimester. Prenatal diagnosis 69 10820406
1994 Serum PAPP-A and free beta-hCG are first-trimester screening markers for Down syndrome. Prenatal diagnosis 67 7533285
2010 Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility. Biology of reproduction 62 20130263
2018 CircRNA-0004904, CircRNA-0001855, and PAPP-A: Potential Novel Biomarkers for the Prediction of Preeclampsia. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 61 29758559
2006 PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. American journal of obstetrics and gynecology 58 16635455
2008 Pregnancy-associated plasma protein-A (PAPP-A) and cardiovascular risk. Atherosclerosis 56 18789800
2019 Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion. Journal of the National Cancer Institute 54 30698726
2018 IGFBP-4 and PAPP-A in normal physiology and disease. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 54 29864720
2014 Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. Oncotarget 51 24572990
2016 PAPP-A and the IGF system. Annales d'endocrinologie 49 27155776
2008 First trimester maternal serum PAPP-A, beta-hCG and ADAM12 in prediction of small-for-gestational-age fetuses. Prenatal diagnosis 49 19003798
2023 The Pregnancy-Associated Plasma Protein-A (PAPP-A) Story. Endocrine reviews 48 37267421
2016 mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging cell 48 27618784
2012 First Trimester Maternal Serum Screening Using Biochemical Markers PAPP-A and Free β-hCG for Down Syndrome, Patau Syndrome and Edward Syndrome. Indian journal of clinical biochemistry : IJCB 44 24381414
2018 PAPP-A and cancer. Journal of molecular endocrinology 43 29844094
2020 PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans. Science translational medicine 42 33239385
2023 The Stanniocalcin-PAPP-A-IGFBP-IGF Axis. The Journal of clinical endocrinology and metabolism 40 36718521
2019 The association between first trimester AFP to PAPP-A ratio and placentally-related adverse pregnancy outcome. Placenta 40 31138428
2006 Modulation of PAPP-A expression by PPARgamma in human first trimester trophoblast. Placenta 40 16388849
2014 Pregnancy-associated plasma protein A (PAPP-A) and preeclampsia. Advances in clinical chemistry 39 24783354
2003 Expression of pregnancy-associated plasma protein-A (PAPP-A) during human villous trophoblast differentiation in vitro. Placenta 39 12744930
1981 Pregnancy-associated plasma protein-A (PAPP-A) and hCG in early pregnancy. British journal of obstetrics and gynaecology 34 6169364
2024 The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA. Developmental cell 32 38484732
2015 Combination of PAPPA, fhCGβ, AFP, PlGF, sTNFR1, and Maternal Characteristics in Prediction of Early-onset Preeclampsia. Clinical medicine insights. Reproductive health 31 26106266
2015 PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. Oncotarget 30 26336825
2013 Variation of papp-a level in the first trimester of pregnancy and its clinical outcome. Journal of obstetrics and gynaecology of India 30 24757339
2016 PAPP-A, IGFBP-4 and IGF-II are secreted by human adipose tissue cultures in a depot-specific manner. European journal of endocrinology 29 27585595
2016 PAPP-A: a promising therapeutic target for healthy longevity. Aging cell 29 28035757
2022 Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nature communications 28 36257932
2020 Chimeric RNA ASTN2-PAPPAas aggravates tumor progression and metastasis in human esophageal cancer. Cancer letters 28 33388371
2017 Nuchal translucency measurement, free β-hCG and PAPP-A concentrations in IVF/ICSI pregnancies: systematic review and meta-analysis. Prenatal diagnosis 28 28419502
2014 PAPP-A and IGFBP-4 fragment levels in patients with ST-elevation myocardial infarction treated with heparin and PCI. Clinical biochemistry 28 25489725
2010 Pregnancy associated plasma protein-A (PAPP-A) is not a marker of the vulnerable atherosclerotic plaque. Clinical biochemistry 28 21185276
2006 [Inflammation, atherosclerosis and cardiovascular disease risk: PAPP-A, Lp-PLA2 and cystatin C. New insights or redundant information?]. Revista espanola de cardiologia 28 16712749
2016 Maternal serum PAPP-A and free β-hCG at 12, 22 and 32 weeks' gestation in screening for pre-eclampsia. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 27 26726121
2013 Pregnancy-associated plasma protein A (PAPP-A) modulates the early developmental rate in zebrafish independently of its proteolytic activity. The Journal of biological chemistry 26 23430244
2020 Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. JCI insight 25 31990681
1993 Assignment of the human gene for pregnancy-associated plasma protein A (PAPPA) to 9q33.1 by fluorescence in situ hybridization to mitotic and meiotic chromosomes. Cytogenetics and cell genetics 25 7679961
2018 Placental expression of PAPPA, PAPPA-2 and PLAC-1 in pregnacies is associated with FGR. Molecular medicine reports 24 29532882
2014 Preferential expression of PAPPA in human preadipocytes from omental fat. The Journal of endocrinology 24 24781252
2010 PAPP-A: a new anti-aging target? Aging cell 24 20854420
2020 First trimester PAPP-A serum levels and long-term metabolic outcome of mothers and their offspring. Scientific reports 23 32198414
2020 MiR-182-5p Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by ox-LDL Through Targeting PAPPA. International heart journal 23 32684596
2013 Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy. The Journal of endocrinology 23 23881937
2002 Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 23 12213189
2019 Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2. Breast cancer research : BCR 22 31046834
2011 βhCG and PAPP-A in first trimester: predictive factors for preeclampsia? Hypertension in pregnancy 22 22148978
2010 Free leptin index and PAPP-A: a first trimester maternal serum screening test for pre-eclampsia. Prenatal diagnosis 22 20013873
2019 PAPP-A and the IGF system in atherosclerosis: what's up, what's down? American journal of physiology. Heart and circulatory physiology 21 31518159
2012 PP13 and PAPP-A in the First and Second Trimesters: Predictive Factors for Preeclampsia? ISRN obstetrics and gynecology 21 22778981
2018 Characterization of mouse pericardial fat: regulation by PAPP-A. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 20 30025286
2015 ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts. Cell adhesion & migration 20 26417939
2013 Development of a recombinant antibody towards PAPP-A for immunohistochemical use in multiple animal species. Journal of immunological methods 20 24333852
2007 Measurement and clinical significance of circulating PAPP-A in ACS patients. Clinica chimica acta; international journal of clinical chemistry 20 17376420
2007 PAPP-A: a possible pathogenic link to the instability of atherosclerotic plaque. Medical hypotheses 20 17714879
2002 Pregnancy-associated plasma protein A (PAPP-A): theoretical and clinical aspects. Bratislavske lekarske listy 20 12448565
2012 Role of PAPP-A in aging and age-related disease. Experimental gerontology 19 22790018
2012 PAPP-A in cardiac and non-cardiac conditions. Clinica chimica acta; international journal of clinical chemistry 19 23262366
2019 PAPP-A concentrations change in patients with gestational diabetes. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 18 31335241
2022 Pregnancy-associated plasma protein-A (PAPPA) promotes breast cancer progression. Bioengineered 17 34974815
2015 Involvement of PAPP-A and IGFR1 in Cystic Ovarian Disease in Cattle. Reproduction in domestic animals = Zuchthygiene 17 26031184
2021 First trimester serum PAPP-A is associated with placenta accreta: a retrospective study. Archives of gynecology and obstetrics 16 33515274
2016 First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies. Clinical chemistry and laboratory medicine 16 26544105
2015 Placental DNA methylation at term reflects maternal serum levels of INHA and FN1, but not PAPPA, early in pregnancy. BMC medical genetics 16 26654447
2003 Frequency and clinical consequences of extremely high maternal serum PAPP-A levels. Prenatal diagnosis 16 12749035
2022 Pregnancy-associated plasma protein-A (PAPP-A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis. Journal of cellular physiology 15 35098542
2017 Maternal Serum PLGF, PAPPA, β-hCG and AFP Levels in Early Second Trimester as Predictors of Preeclampsia. Clinical laboratory 15 28627818
2021 Knockdown of H19 Attenuates Ox-LDL-induced Vascular Smooth Muscle Cell Proliferation, Migration, and Invasion by Regulating miR-599/PAPPA Axis. Journal of cardiovascular pharmacology 14 33235026
2019 A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins. Scientific reports 14 31519945
2017 Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis. Metabolism: clinical and experimental 14 28964325
2016 PAPP-A in normal human mesangial cells: effect of inflammation and factors related to diabetic nephropathy. The Journal of endocrinology 14 27519211
2021 Suppression of PAPP-A mitigates atherosclerosis by mediating macrophage polarization via STAT3 signaling. Biochemical and biophysical research communications 13 33508770
2017 Pregnancy-associated plasma protein-A (PAPP-A) levels in patients with severe allergic asthma are reduced by omalizumab. The Journal of asthma : official journal of the Association for the Care of Asthma 13 29211611
2011 PAPP-A and free β-hCG measured prior to 10 weeks is associated with preterm delivery and small-for-gestational-age infants. Prenatal diagnosis 13 21268036
2011 PAPP-A and free β-hCG in relation to admission to neonatal intensive care unit and neonatal disease. Prenatal diagnosis 13 22021032
1983 Pregnancy-associated plasma protein-A (PAPP-A) inhibits thrombin-induced coagulation of plasma. Thrombosis research 13 6197764
2023 Exosomes Promote Atherosclerosis Progression by Regulating Circ_100696/miR-503-5p/PAPPA Axis-Mediated Vascular Smooth Muscle Cells Proliferation and Migration. International heart journal 12 37778995
2022 Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition. Nature communications 12 36127359
2021 Inhibition of longevity regulator PAPP-A modulates tissue homeostasis via restraint of mesenchymal stromal cells. Aging cell 12 33561324
2020 Long non-coding RNA MIAT/miR-148b/PAPPA axis modifies cell proliferation and migration in ox-LDL-induced human aorta vascular smooth muscle cells. Life sciences 12 32470448
2007 Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease. Biological chemistry 12 17976018
2024 First-Trimester PlGF and PAPP-A and the Risk of Placenta-Mediated Complications: PREDICTION Prospective Study. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 11 39631521
2021 Predictive value of PAPP-A for ectopic pregnancy and analysis of related factors. Experimental and therapeutic medicine 11 34093757
2021 lncRNA PAPPA-AS1 Induces the Development of Hypertrophic Scar by Upregulating TLR4 through Interacting with TAF15. Mediators of inflammation 11 34285657
2020 The Multi-Faced Role of PAPP-A in Post-Partum Breast Cancer: IGF-Signaling is Only the Beginning. Journal of mammary gland biology and neoplasia 11 32901383
2019 Collagen and PAPP-A in the Etiology of Postpartum Breast Cancer. Hormones & cancer 11 31631239
2011 PAPP-A levels of late pregnancy in preeclampsia and HELLP syndrome. Archives of gynecology and obstetrics 11 21533533
1984 Pregnancy-associated plasma protein A (PAPP-A) in non-pregnant subjects. British journal of obstetrics and gynaecology 11 6202314
2023 Higher PAPP-A Values in Pregnant Women Complicated with Preeclampsia Than with Gestational Hypertension. Reproductive sciences (Thousand Oaks, Calif.) 10 36917422
2022 First trimester low maternal serum pregnancy associated plasma protein-A (PAPP-A) as a screening method for adverse pregnancy outcomes. Journal of perinatal medicine 10 36131518
2020 Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease. Cellular signalling 10 32569826
2020 Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice. Endocrinology 10 32888014
2012 CRP and TNF-α  induce PAPP-A expression in human peripheral blood mononuclear cells. Mediators of inflammation 10 22997483

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