The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

Acosta, Helena; Iliev, Dobromir; Grahn, Tan Hooi Min; Gouignard, Nadège; Maccarana, Marco; Griesbach, Julia; Herzmann, Svende; Sagha, Mohsen; Climent, María; Pera, Edgar M.

doi:10.1242/dev.113886

Cited by 14 publications

(46 citation statements)

References 52 publications

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“…ERK activation drives the induction of downstream transcriptional effectors with direct impact on chondrocyte physiology, as MMP13 [ 23 , 27 , 28 ]. To note, our results are in agreement with those obtained by Acosta et al [ 29 ] and by Pagliara et al [ 14 ]. MAPKs, such as ERK 1/2, may activate different downstream transcription factors, for instance NF-κB, which mediates much of the downstream effects of IL-1, including the induction of MMPs and other pro-inflammatory cytokines.…”

Section: Discussionsupporting

confidence: 94%

SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways

et al. 2015

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ObjectivesOsteoarthritis (OA) is a chronic joint disease, characterized by a progressive loss of articular cartilage. During OA, proinflammatory cytokines, such as interleukin IL-1, induce the expression of matrix metalloproteinases (MMPs) in chondrocytes, contributing thus to the extracellular matrix (ECM) degradation. Members of Serpine family, including plasminogen activator inhibitors have been reported to participate in ECM regulation. The aim of this study was to assess the expression of serpin peptidase inhibitor clade E member 2 (SERPINE2), under basal conditions and in response to increasing doses of IL-1α, in human cultured chondrocytes. We also examined the effects of SERPINE2 on IL-1α-induced MMP-13 expression. For completeness, the signaling pathway involved in this process was also explored.MethodsSERPINE2 mRNA and protein expression were evaluated by RT-qPCR and western blot analysis in human T/C-28a2 cell line and human primary chondrocytes. These cells were treated with human recombinant SERPINE2, alone or in combination with IL-1α. ERK 1/2, NFκB and AP-1 activation were assessed by western blot analysis.ResultsHuman cultured chondrocytes express SERPINE2 in basal condition. This expression increased in response to IL-1α stimulation. In addition, recombinant SERPINE2 induced a clear inhibition of MMP-13 expression in IL-1α-stimulated chondrocytes. This inhibitory effect is likely regulated through a pathway involving ERK 1/2, NF-κB and AP-1.ConclusionsTaken together, these data demonstrate that SERPINE2 might prevent cartilage catabolism by inhibiting the expression of MMP-13, one of the most relevant collagenases, involved in cartilage breakdown in OA.

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Section: Discussionsupporting

confidence: 94%

SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways

et al. 2015

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“…PN-1 has been shown to promote metastasis in various human cancers by multiple mechanisms such as by remodeling the tumor matrix and polarizing tumor-associated macrophages 39 , activating glycogen synthesis kinase 3β (GSK-3β) signaling pathway 40 , and activating P38 signaling pathways 41 . PN-1 was reported to be up-regulated by oncogenic activation of Ras, BRAF and MEK and contributes to pro-neoplastic actions of ERK signaling in colorectal cancer cells 42 . However, how PN-1 is regulated in breast cancer cells remains largely unclear.…”

Section: Discussionmentioning

confidence: 99%

Protease Nexin I is a feedback regulator of EGF/PKC/MAPK/EGR1 signaling in breast cancer cells metastasis and stemness

Tang

Zhu

et al. 2019

Cell Death Dis

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Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, which are the radical cause of drug resistance, tumor relapse, and metastasis in breast cancer. The extracellular serine protease inhibitor serpinE2, also named protease nexin-1 (PN-1), contributes to enhanced metastasis of cancer cells mainly by remodeling the tumor matrix. In this study, we found that PN-1 was up-regulated in breast cancer, which promoted cell invasion, migration and stemness. Furthermore, by using specific inhibitors, we discovered that epidermal growth factor (EGF) up-regulated PN-1 in breast cancer cells through cascade activation of epidermal growth factor receptor (EGFR) to the activation of protein kinase Cδ (PKCδ), mitogen-activated protein kinase (MEK) and extracellular signal-related kinase (ERK), which finally led to the up-regulation of early growth response protein 1 (EGR1). Moreover, EGF signaling was further activated as a feedback of PN-1 up-regulation through PN-1 blocking HtrA1. Taken together, our findings revealed a novel signaling axis that up-regulated PN-1 expression in breast cancer cells, and the new mechanism of PN-1-promoted breast cancer metastasis, which may provide new insights into identifying novel therapeutic targets for breast cancer.

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“…A cluster of proteins involved in posttranslational modification, protein turnover, and chaperones displayed significant differential expression. These proteins, including GDN 20 , serine protease inhibitor A3N 21 , heparin cofactor 2 22 , PCSK9 23 , hyaluronan-binding protein 2 24 and protein disulfide-isomerase (PDI) 25 , play important roles in embryonic development and participate in cellular processes and signaling. PCSK9 was also reported to be associated with neuronal development 23 .…”

Section: Discussionmentioning

confidence: 99%

Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics

Wei

et al. 2015

Sci Rep

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To identify candidate serum molecule biomarkers for the non-invasive early prenatal diagnosis of neural tube defects (NTDs), we employed an iTRAQ-based quantitative proteomic approach to analyze the proteomic changes in serum samples from embryonic day (E) 11 and E13 pregnant rats with spina bifida aperta (SBA) induced by all-trans retinoic acid. Among the 390 proteins identified, 40 proteins at E11 and 26 proteins at E13 displayed significant differential expression in the SBA groups. We confirmed 5 candidate proteins by ELISA. We observed the space-time expression changes of proprotein convertase subtilisin/kexin type 9 (PCSK9) at different stages of fetal development, including a marked decrease in the sera of NTD pregnancies and gradual increase in the sera of normal pregnancies with embryonic development. PCSK9 demonstrated the diagnostic efficacy of potential NTD biomarkers [with an area under the receiver operating characteristic curve of 0.763, 95% CI: 065–0.88]. Additionally, PCSK9 expression in the spinal cords and placentas of SBA rat fetuses was markedly decreased. PCSK9 could serve as a novel molecular biomarker for the non-invasive prenatal screening of NTDs and may be involved in the pathogenesis of NTDs at critical periods of fetal development.

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The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

Cited by 14 publications

References 52 publications

SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways

SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways

Protease Nexin I is a feedback regulator of EGF/PKC/MAPK/EGR1 signaling in breast cancer cells metastasis and stemness

Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics

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