Evidence that Furin Is an Authentic Transforming Growth Factor-β1-Converting Enzyme

Dubois, Claire M.; Blanchette, François; Laprise, Marie-Hélène; Leduc, Richard; Grondin, Francine; Seidah, Nabil G.

doi:10.1016/s0002-9440(10)63970-3

Cited by 224 publications

(205 citation statements)

References 82 publications

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“…Interestingly, the data showed that the expression of only furin among all the PCs can be modulated by its cleavage product, TGF-b1, which can coordinately increase the transcription of furin and TGF-b1 precursor. Consistently, only furin is coexpressed with TGF-b1 in the developing heart, bones, and fetal liver [57]. Another study also showed that Emilin1 can inhibit TGFb1-induced signaling by preventing its furin-mediated cleavage, which is associated with decreased BP [58].…”

Section: Furin May Regulate Bp By Modulation Of Transforming Growth Fmentioning

confidence: 80%

“…Then, proteolytic cleavage is required for its activation. Evaluation of the cleavage sites revealed a unique R-H-R-R sequence that is cleaved by furin [57]. In furinpositive BSC-40 cells, treatment with a1-PDX markedly blocked the maturation of TGF-b1 precursor.…”

Section: Furin May Regulate Bp By Modulation Of Transforming Growth Fmentioning

confidence: 97%

“…Evidence from multiple sources indicates that experimental modulation of TGF-b activities or TGF-b responses changes the course of atherosclerosis and intimal hyperplasia [83]. Furin is an authentic and adaptive enzyme that can convert TGF-b [57]. In adventitial and intimal areas of arteries, the levels of phosphorylated Smad 1/5 and 2/3, MT1-MMP, MMP-2 and furin are increased after balloon dilation.…”

Section: Furin Promotes Cell Proliferation and Ecm Synthesis By Activmentioning

confidence: 99%

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Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

2017

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Section: Furin May Regulate Bp By Modulation Of Transforming Growth Fmentioning

confidence: 80%

Section: Furin May Regulate Bp By Modulation Of Transforming Growth Fmentioning

confidence: 97%

Section: Furin Promotes Cell Proliferation and Ecm Synthesis By Activmentioning

confidence: 99%

See 1 more Smart Citation

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

2017

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“…TGFB1 directly induces Furin expression in rodents, which is a prerequisite for its functional maturation and anti-inflammatory function (18,38). Consequently, the autoimmune phenotype of CD4cre-fur fl/fl mice can be chiefly attributed to a lack of bioavailable, T cell-produced TGFB1.…”

Section: Resultsmentioning

confidence: 99%

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

et al. 2015

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Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinA td204e/؉ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinuminfected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinA td204e/؉ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinA td204e/؉ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.T uberculosis (TB) is an epidemic infectious disease caused by the mycobacterial species Mycobacterium tuberculosis (1, 2). Circa 13% of the individuals with active TB were simultaneous carriers of the human immunodeficiency virus (HIV), and almost one-third of TB-associated deaths occurred among HIV ϩ patients, demonstrating the critical role of cluster of differentiation 4 (CD4 ϩ ) T lymphocyte-mediated immunity in the control of M. tuberculosis infection (3, 4). More specifically, the adaptive immunity against TB is primarily mediated by T helper (Th) type 1 cells, as is suggested by the gene expression profile upon infection (5), as well as the infection-induced mortality of gamma interferon-deficient (6, 7) and interleukin-12 (IL-12)-deficient (8) mice.The proprotein convertase subtilisin/kexin (PCSK) enzymes are a family of serine endoproteases with nine members in humans: PCSK1 and -2, FURIN, PCSK4 to -7, membrane-bound transcription factor peptidase site 1 (MBTPS1), and PCSK9 (9). Typically, PCSKs convert precursor proteins (proproteins) into their biologically active forms by cleaving them at specific target motifs made up of the basic amino acids lysine and arginine (9, 10). FURIN was the first identified mammalian PCSK and is present in vertebrates and many invertebrates (11,12). A series of in vitro experiments have suggested a central role for FURIN in host defense because it proteolytically activates several immunoregulatory proproteins, such as membrane-inserted matrix metallo...

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“…38 Besides TGF-b1 furin cleaves for example b-nerve growth factor, bone morphogenetic protein-4, membrane-type 1 matrix metalloproteinase, the a-and b-secretases associated with Alzheimer's disease and bacterial toxins. [42][43][44] Cleavage of these substrates occurs at the TGN but is not limited to this compartment. Furin cycles between the TGN and the cell surface, where it can process different substrates.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

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The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein stability of the a-subunit of the hypoxiainducible factor-1 (HIF-1), which mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating HIF-1a hydroxylation and thus stability in normoxia. In human cancers, HIF-1a is overexpressed as a result of intratumoral hypoxia which in turn promotes tumor progression. The role of PHD2 for tumor progression is in contrast far from being thoroughly understood. Therefore, we established PHD2 knockdown clones of MDA-MB-231 breast cancer cells and analyzed their tumorforming potential in a SCID mouse model. Tumor progression was significantly impaired in the PHD2 knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing PHD2 expression. In a RNA profile screen, we identified the secreted phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was additionally verified in 294 invasive breast cancer biopsies. In subsequent analyses, we identified that PHD2 alters the processing of transforming growth factor (TGF)-b1, which is highly involved in SPP1 expression. The altered processing capacity was associated with a dislocation of the pro-protein convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might affect tumor-relevant TGF-b1 target gene expression by altering the TGF-b1 processing capacity.

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Evidence that Furin Is an Authentic Transforming Growth Factor-β1-Converting Enzyme

Cited by 224 publications

References 82 publications

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

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