Cell Surface Targeting of Pregnancy-associated Plasma Protein A Proteolytic Activity

Laursen, Lisbeth S.; Overgaard, Michael Toft; Weyer, Kathrin; Boldt, Henning B.; Ebbesen, Peter; Christiansen, Michael; Sottrup‐Jensen, Lars; Giudice, Linda C.; Oxvig, Claus

doi:10.1074/jbc.m209155200

Cited by 100 publications

(76 citation statements)

References 52 publications

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“…2C), suggesting that proMBP is not a typical C-type lectin. Heparan sulfate GAGs compete with the PAPP-A receptor for PAPP-A surface binding (11). However, we find that under experimental conditions where no covalent complex is formed, excess proMBP did not affect PAPP-A surface binding (Fig.…”

Section: Discussionmentioning

confidence: 65%

“…Heparan sulfate GAG has previously been reported to abrogate PAPP-A surface binding to an unknown heparan sulfate proteoglycan (11). We used flow cytometry to analyze to ability of PAPP-A to interact with this molecule.…”

Section: Abrogation Of Papp-a Surface Binding Requires the Prombp Gag-mentioning

confidence: 99%

“…The binding of PAPP-A to an unknown heparan sulfate proteoglycan directs its proteolytic activity to the surface of cells (11), suggesting that surface binding controls PAPP-A-mediated IGF release and consequently IGF signaling spatially. Mapping experiments localized the site responsible for specific surface binding to complement control protein (CCP) modules 3 and 4 in the C-terminal region of PAPP-A, which contains five consecutive CCP modules (11,12).…”

mentioning

confidence: 99%

“…Mapping experiments localized the site responsible for specific surface binding to complement control protein (CCP) modules 3 and 4 in the C-terminal region of PAPP-A, which contains five consecutive CCP modules (11,12). These modules, originally known from proteins associated with the complement system, are responsible for interactions with glycosaminoglycans (GAGs) in several other proteins (13,14).…”

mentioning

confidence: 99%

“…bikunin, a component of inter-␣-trypsin inhibitor, which is substituted with a chondroitin sulfate GAG that functions to bind the additional subunits (25). The function of the proMBP GAG is unknown, but the PAPP-A⅐proMBP complex does not exhibit cell surface binding, and surface binding can be regained after the treatment of the PAPP-A⅐proMBP complex with heparinase (11).…”

mentioning

confidence: 99%

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Cell Surface Detachment of Pregnancy-associated Plasma Protein-A Requires the Formation of Intermolecular Proteinase-Inhibitor Disulfide Bonds and Glycosaminoglycan Covalently Bound to the Inhibitor

Glerup

Kløverpris

Laursen

et al. 2007

Journal of Biological Chemistry

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The metzincin metalloproteinase pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1) promotes cell growth by proteolytic cleavage of insulin-like growth factorbinding proteins 4 and 5, causing the release of bound insulin-like growth factors. PAPP-A binds an unknown cell-surface heparan sulfate proteoglycan, suggesting that it controls insulin-like growth factor signaling spatially. In human pregnancy, the majority of PAPP-A circulates as a disulfidebonded complex with its inhibitor, the proform of eosinophil major basic protein (proMBP). Interestingly, Ser-62 of proMBP is substituted with a glycosaminoglycan (GAG) chain, possibly a heparan sulfate type, and the PAPPA⅐proMBP complex is unable to bind to the cell surface. We show here that proMBP detaches surface-bound PAPP-A in a process that depends on the proMBP GAG and also on the formation of intermolecular disulfide bonds between PAPP-A and proMBP. Unlike what was expected, we demonstrate that the GAG of proMBP is not required for PAPPA⅐proMBP complex formation and that proMBP residues His-137, Ser-178, Arg-179, and Asn-181 are important for the recognition of PAPP-A. Using a mouse model, we find that the half-life of circulating PAPP-A and proMBP in complex is severalfold higher than both of the uncomplexed proteins, further suggesting that the PAPP-A⅐proMBP complex is formed at the cell surface in vivo rather than in the circulation. Further supporting this, we show that formation of the PAPP-A⅐proMBP complex at the cell surface proceeds rapidly compared with the slow rate of complex formation in solution. Because both PAPP-A and proMBP are expressed ubiquitously, this model may be applicable to many tissues in which insulin-like growth factor bioavailability is locally regulated.

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Section: Discussionmentioning

confidence: 65%

Section: Abrogation Of Papp-a Surface Binding Requires the Prombp Gag-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cell Surface Detachment of Pregnancy-associated Plasma Protein-A Requires the Formation of Intermolecular Proteinase-Inhibitor Disulfide Bonds and Glycosaminoglycan Covalently Bound to the Inhibitor

Glerup

Kløverpris

Laursen

et al. 2007

Journal of Biological Chemistry

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Pregnancy‐associated plasma protein‐A proteolytic activity in rat vertebral cell cultures: Stimulation by dexamethasone–a potential mechanism for glucocorticoid regulation of osteoprogenitor proliferation and differentiation

Heersche

2005

Journal Cellular Physiology

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Glucocorticoids (GCs) at physiological concentrations stimulate osteoprogenitor proliferation and differentiation in rat bone cell populations, and this is mediated in part by an increased response to insulin-like growth factors (IGFs). Since IGF binding proteins (IGFBPs) modulate IGF actions, we evaluated whether the increased IGF responsiveness might be associated with decreased inhibitory IGFBP-4 peptide levels. Rat vertebral cells were cultured for up to 20 days with or without dexamethasone (Dex). Cell layer proteins were extracted at day 6, 8, 14, and 20, conditioned media (CM) collected at day 8, 14, and 20, and total RNA isolated at day 14 and 20 of culture. Western blotting showed that cell layer IGFBP-4 levels were lower, while IGFBP-4 protease activity in CM was higher, in Dex-treated cultures. Addition of pregnancy-associated plasma protein-A (PAPP-A) antibody to CM abrogated IGFBP-4 proteolysis. PAPP-A mRNA levels were the same in control and Dex-treated cultures as evaluated by RT-PCR. Our data demonstrate that activity of the IGFBP-4 protease, PAPP-A, in rat bone cell cultures is increased by Dex via post-transcriptional mechanisms. Since IGFBP-4 mRNA levels in Dex-treated cultures were the same as in controls at day 8, slightly lower than in controls at day 14, and higher than in controls at day 20 as shown previously, the decreased IGFBP-4 peptide levels in Dex-treated cultures likely result from increased IGFBP-4 proteolysis by the elevated PAPP-A enzymatic activity. Our findings underscore a novel mechanism whereby GCs increase IGF responses in rat bone cells via PAPP-A-induced IGFBP-4 proteolysis.

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Pregnancy‐associated plasma protein‐A (PAPP‐A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis

Bale¹,

Schafer

Atkinson³

et al. 2022

Journal Cellular Physiology

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few effective treatment options. We found a highly significant correlation between pregnancy‐associated plasma protein (PAPP)‐A expression in IPF lung tissue and disease severity as measured by various pulmonary and physical function tests. PAPP‐A is a metalloproteinase that enhances local insulin‐like growth factor (IGF) activity. We used primary cultures of normal adult human lung fibroblasts (NHLF) to test the hypothesis that PAPP‐A plays an important role in the development of pulmonary fibrosis. Treatment of NHLF with pro‐fibrotic transforming growth factor (TGF)‐β stimulated marked increases in IGF‐I mRNA expression (>20‐fold) and measurable IGF‐I levels in 72‐h conditioned medium (CM). TGF‐β treatment also increased PAPP‐A levels in CM fourfold (p = 0.004) and proteolytic activity ~2‐fold. There was an indirect effect of TGF‐β to stimulate signaling through the PI3K/Akt pathway, which was significantly inhibited by both IGF‐I‐inactivating and PAPP‐A inhibitory antibodies. Induction of senescence in NHLF increased PAPP‐A levels in CM 10‐fold (p = 0.006) with attendant increased proteolytic activity. Thus, PAPP‐A is a novel component of the senescent lung fibroblast secretome. In addition, NHLF secreted extracellular vehicles (EVs) with surface‐bound active PAPP‐A that were increased fivefold with senescence. Regulation of PAPP‐A and IGF signaling by TGF‐β and cell senescence suggests an interactive cellular mechanism underlying the resistance to apoptosis and the progression of fibrosis in IPF. Furthermore, PAPP‐A‐associated EVs may be a means of pro‐fibrotic, pro‐senescent communication with other cells in the lung and, thus, a potential therapeutic target for IPF.

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Cell Surface Targeting of Pregnancy-associated Plasma Protein A Proteolytic Activity

Cited by 100 publications

References 52 publications

Cell Surface Detachment of Pregnancy-associated Plasma Protein-A Requires the Formation of Intermolecular Proteinase-Inhibitor Disulfide Bonds and Glycosaminoglycan Covalently Bound to the Inhibitor

Cell Surface Detachment of Pregnancy-associated Plasma Protein-A Requires the Formation of Intermolecular Proteinase-Inhibitor Disulfide Bonds and Glycosaminoglycan Covalently Bound to the Inhibitor

Pregnancy‐associated plasma protein‐A proteolytic activity in rat vertebral cell cultures: Stimulation by dexamethasone–a potential mechanism for glucocorticoid regulation of osteoprogenitor proliferation and differentiation

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis

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