Processing of Transforming Growth Factor β1 Precursor by Human Furin Convertase

Dubois, Claire M.; Laprise, Marie-Hélène; Blanchette, François; Gentry, L E; Leduc, Richard

doi:10.1074/jbc.270.18.10618

Cited by 369 publications

(286 citation statements)

References 67 publications

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“…TNF␣ activates the release of membrane-bound BLyS from invading neutrophils at sites of inflammation, and this shedding is furin mediated (152). Furin can also generate active TGF␤, which in turn increases furin expression (153). In fibroblastlike synoviocytes, TGF␤ increases ADAMTS-4 expression (154), such that a positive feedback loop is created, with increased levels of active ADAMTS-4 and aggrecanolysis (145).…”

Section: Pro-protein Convertases (Pcs)mentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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Section: Pro-protein Convertases (Pcs)mentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…The thin bars define the epitopes recognized by MON 139, 148, 150, and 152 antibodies, the darker bars the predicted antigenic regions (15). (27), and parathyroid hormone-related protein (22) are also processed by furin. Stromelysin-3, a metalloprotease involved in mammary tissue remodeling, was activated by furin in cells and in solution (29).…”

Section: Discussionmentioning

confidence: 99%

Secretion of Human Furin into Mouse Milk

Paleyanda

Drews

Lee

et al. 1997

Journal of Biological Chemistry

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We have previously described the expression of the human proprotein convertase furin or paired basic amino acid-cleaving enzyme, in mice transgenic for paired basic amino acid-cleaving enzyme and human Protein C (HPC). Here we show 100-fold or higher expression of furin in the mammary gland, compared with endogenous furin. Furin and recombinant HPC were detected in the same regions of the mammary gland and regulated similar to the endogenous whey acidic protein. In addition to the expected intracellular localization, furin was secreted into the milk as an 80-kDa form lacking the transmembrane and cytoplasmic domains. Furin present at levels of up to 40,000 units/ml milk cleaved the t-butoxycarbonyl-RVRR-AMC substrate with a K m of 32 M, and processed the recombinant HPC precursor at the appropriate sites. Surprisingly, the expression of an active protease was not toxic to the mammary gland. This is a rare example of an animal model secreting active truncated forms of a processing endoprotease into a bodily fluid.Furin or paired basic amino acid cleaving enzyme (PACE) 1 is a Ca 2ϩ -dependent serine protease that processes proteins in the constitutive secretory pathway (1). Furin belongs to a family of subtilisin-like proprotein convertases including kexin (EC 3.4.21.61), PC1/3, PC2, PC4, PC5/6, PACE4 (reviewed in Ref. 1), and PC7/PC8 or lymphoma proprotein convertase (2-5), that play a role in the maturation of proproteins by cleavage at dibasic or tetrabasic sites (6). Unlike PC1/3, PC2, and PC4, which are restricted to endocrine, neural, or testicular germ cells and ovaries, respectively, the furin gene is expressed in most cells and tissues examined (1, 7).cDNAs cloned from several species show furin to contain prepro-, catalytic and middle domains, a cysteine-rich region, transmembrane anchor, and cytoplasmic domain (1). Furin is activated by autocatalytic cleavage of its propeptide, presumably at the -Lys-Arg-Arg-Thr-Lys-Arg Ϫ1 -2 site (1,8). A membrane-associated protein, it is found mainly in the trans-Golgi network (TGN) co-localized with the TGN 38 marker protein (9). Some amount of furin recycles between the cell surface and the TGN (9) in endosome-like structures (10). So far furin has not been detected in bodily fluids like blood, nor has the effect of its expression on cell and organ development been studied in transgenic animals.Transgenic animals secreting recombinant proteins into milk, blood, urine, or saliva (11) have been generated and differences in recombinant protein modification compared with the human counterpart observed (12). In a pioneering attempt to engineer the post-translational capacity of the mouse mammary gland, we reported enhanced proteolytic maturation of the recombinant human Protein C (rHPC) precursor upon coexpression with furin (13). However, the effect of increased furin concentration on mammary gland development could not be predicted, nor its' intra-and extracellular distribution. Here we demonstrate localization of two heterologous proteins with the endogenous whey ac...

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“…The TGFb ligands are synthesized within the cell as dimeric pro-hormones [17]. Latent dimeric forms are secreted into the extracellular matrix, where they are cleaved by furins and other convertases to form active signaling molecules [18,19]. Activated TGFb cytokines can then signal by bringing together two pairs of receptor serine/threonine kinases, the type I and type II receptors, forming a heteromeric complex.…”

Section: Tgfβ Signalingmentioning

confidence: 99%

Roles of TGFβ in metastasis

2008

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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in preclinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.

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Processing of Transforming Growth Factor β1 Precursor by Human Furin Convertase

Cited by 369 publications

References 67 publications

Emerging roles of serine proteinases in tissue turnover in arthritis

Emerging roles of serine proteinases in tissue turnover in arthritis

Secretion of Human Furin into Mouse Milk

Roles of TGFβ in metastasis

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