Stanniocalcin-1 Potently Inhibits the Proteolytic Activity of the Metalloproteinase Pregnancy-associated Plasma Protein-A

Kløverpris, Søren; Mikkelsen, Jakob Guldbæk; Pedersen, Josefine H.; Jepsen, Malene R.; Laursen, Lisbeth S.; Petersen, Steen V.; Oxvig, Claus

doi:10.1074/jbc.m115.650143

Cited by 79 publications

(71 citation statements)

References 57 publications

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“…Recently, stanniocalcin‐1 (STC1) (Kløverpris et al , ) and stanniocalcin‐2 (STC2) (Jepsen et al , ) were discovered as potent proteinase inhibitors of PAPP‐A and PAPP‐A2, and accordingly, our knowledge on their connection with the IGF system is novel. While STC2 binds PAPP‐A and PAPP‐A2 irreversibly by the formation of a covalent bond, STC1 binds non‐covalently but with picomolar (pM) affinity.…”

Section: The Igf System In Human Growthmentioning

confidence: 99%

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology

et al. 2017

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The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin‐like growth factor (IGF)‐1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery of mutations in members of this axis. This review focuses on the most recent discovery: mutations in the metalloproteinase pregnancy‐associated plasma protein‐A2 (PAPP‐A2), one of the proteases involved in liberating IGF‐1 from the complexes in which it circulates, in patients with delayed growth failure. We also discuss the advances in the stanniocalcins (STC1 and STC2), proteins that modulate PAPP‐A2, as well as PAPP‐A. These new advances not only bring us one step closer to understanding the strict spatial and temporal control of this axis in systemic growth and maturation, but also highlight possible therapeutic targets when this system goes awry.

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Section: The Igf System In Human Growthmentioning

confidence: 99%

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology

et al. 2017

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“…The exact roles of STC1 in pregnancy and in the pathogenesis of PE are largely unknown. STC1 was reported to inhibit the proteolytic activity of PAPP-A and PAPP-A2 in vitro (12). Reduced maternal serum PAPP-A levels refer to a high PE risk (21), whereas maternal sera and placental tissues from PE cases show, in contrast, elevated levels of PAPP-A2 (22).…”

Section: Discussionmentioning

confidence: 99%

“…Compared with fish, the mammalian STC1 appears to be involved in more diverse physiological and autocrine/paracrine functions. In female reproductive endocrinology, STC1 modulates ovarian function (6, 7), implantation (8, 9), gestation, and lactation (6, 10–12). The expression of ovarian STC1 increases 15-fold during murine gestation, it is further up-regulated in lactating mice, and the circulating hormone reaches detectable threshold only during pregnancy and lactation (6).…”

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confidence: 99%

“…This is consistent with the pathophysiology of PE, often accompanied with proteinuria and renal failure. Furthermore, a recent study demonstrated that STC1 is a proteinase inhibitor of the pregnancy-associated plasma protein (PAPP)-A and PAPP-A2, modulating IGF signaling (12). Both encoding genes, PAPPA and PAPPA2 , are among the most highly expressed genes in the human placenta (20), and their altered expression has been linked to PE (21, 22).…”

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Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators

Juhanson

Rull

Kikas

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context and Objectives:The study represents the first comprehensive analysis of Stanniocalcin-1 (STC1) hormone in human pregnancy, assessing clinical, lifestyle, and genetic determinants of circulating STC1 at term.Design, Setting, and Participants:Participants included women with (n = 50) and without (n = 316) preeclampsia (PE) at delivery, recruited in the REPROgrammed fetal and/or maternal METAbolism (REPROMETA) study (2006–2011, Estonia). Genetic association analysis combined PE cases (n = 597) and controls (n = 623) from the REPROMETA and Finnish Genetics of Preeclampsia Consortium (2008–2011) studies.Main Outcome Measure(s):Maternal postpartum plasma STC1 was measured by ELISA (n = 366) and placental STC1 gene expression by TaqMan quantitative RT-PCR (n = 120). Genotyping was performed using Sequenom MassArray.Results:Significantly higher STC1 plasma level was measured for the PE (median, 1952 pg/mL; 1030–4284 pg/mL) compared with non-PE group (median, 1562 pg/mL; 423–3781 pg/mL; P = 3.7 × 10−4, Mann-Whitney U test). Statistical significance was enhanced after adjustment for cofactors (linear regression, P = 1.8 × 10−6). STC1 measurements were negatively correlated with maternal smoking. Prepregnancy body mass index had a positive correlation with STC1 only among PE patients (r = 0.45; P = .001). The strongest genetic association with hormone concentrations was detected for STC1 single nucleotide polymorphisms rs3758089 (C allele: minor allele frequency, 5%; linear regression: β = 249.2 pg/mL; P = .014) and rs12678447 (G allele: minor allele frequency, 7%; β = 147.0 pg/mL; P = .082). rs12678447 placental genotypes were significantly associated with STC1 gene expression (P = .014). The REPROMETA/Finnish Genetics of Preeclampsia Consortium meta-analysis suggested an increased risk to develop late-onset PE for the rs12678447 G allele carriers (P = .05; odds ratio = 1.38 [0.98–1.93]).Conclusions:Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone levels.

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“…PAPPA encodes PAPP-A, a secreted metalloproteinase that cleaves IGFBP-4, releasing bioactive IGF-1 that can initiate downstream signaling via the IGF-1R [20]. PAPP-A activity can be inhibited by non-covalent or covalent complex formation with endogenous inhibitors stanniocalcin-1 (STC1) or -2 (STC2), respectively [21,22] ( Figure 3A). To verify that PAPPA was expressed predominantly by CAFs and not by tumor cells, we analyzed PAPPA transcripts by RNAScope.…”

Section: Ilc-specific Expression Of Primary Cancer-associated Fibroblmentioning

confidence: 99%

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

Gómez-Cuadrado

Zhao

Souleimanova

et al. 2020

Preprint

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Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance. Methods:We used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast.Results: 45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets. PAPPA was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. PAPPA encodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis of PAPPA and IGF1 associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identified PAPPA as a potential ILC-specific prognostic marker.Conclusions: This is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.

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Stanniocalcin-1 Potently Inhibits the Proteolytic Activity of the Metalloproteinase Pregnancy-associated Plasma Protein-A

Cited by 79 publications

References 57 publications

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology

Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

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