Evidence that Furin Is an Authentic Transforming Growth Factor-β1-Converting Enzyme
Claire M. Dubois,François Blanchette,Marie-Hélène Laprise,Richard Leduc,Francine Grondin,Nabil G. Seidah +5 more
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TLDR
It is demonstrated for the first time that furin is an authentic and adaptive TGF-beta1-converting enzyme whereas other members of the PC family might substitute or supplement furin activity.Abstract:
Transforming growth factor (TGF)-β1 plays an essential role in cell growth and differentiation. It is also considered as a gatekeeper of immune homeostasis with gene disruption leading to autoimmune and inflammatory diseases. TGF-β1 is produced as an inactive precursor polypeptide that can be efficiently secreted but correct proteolytic cleavage is an essential step for its activation. Assessment of the cleavage site has revealed a unique R-H-R-R sequence reminiscent of proprotein convertase (PC) recognition motifs and has previously demonstrated that this PC-like cleavage site is correctly cleaved by furin, a member of the PC family. Here we report that among PC members, furin more closely satisfies the requirements needed to fulfill the role of a genuine TGF-β1 convertase. Even though six members of the PC family have the ability to cleave TGF-β1, ectopic expression of α1-antitrypsin Portland (α1-AT-PDX), a potent furin inhibitor, blocked 80% of TGF-β1 processing mediated by endogenous enzymes as demonstrated in an in vitro digestion assay. Genetic complementation of a furin-deficient LoVo cell line with the wild-type gene restores the production of mature and bioactivable TGF-β1. Moreover, both furin and TGF-β are coordinately expressed and regulated in vitro and in vivo in the hematopoietic and immune system, an important tissue target. These results demonstrate for the first time that furin is an authentic and adaptive TGF-β1-converting enzyme whereas other members of the PC family might substitute or supplement furin activity. Our study advances our comprehension of the complexity of the TGF-β system and should facilitate the development of therapeutically useful TGF-β inhibitors.read more
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Furin at the cutting edge: from protein traffic to embryogenesis and disease.
TL;DR: This review summarizes various features of furin — its structural and enzymatic properties, intracellular localization, trafficking, substrates, and roles in vivo.
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Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23
Kenneth E. White,Gwenaelle Carn,Gwenaelle Carn,Bettina Lorenz-Depiereux,Bettina Lorenz-Depiereux,Anna Benet-Pagès,Anna Benet-Pagès,Tim M. Strom,Tim M. Strom,Michael J. Econs,Michael J. Econs +10 more
TL;DR: FGF-23 proteins containing the ADHR mutations are secreted, and produce polypeptides less sensitive to protease cleavage than wild-type FGF- 23, thereby potentially elevating circulating concentrations of F GF-23 and leading to phosphate wasting in ADHR patients.
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Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.
Kim Van Roey,Bora Uyar,Robert J. Weatheritt,Holger Dinkel,Markus Seiler,Aidan Budd,Toby J. Gibson,Norman E. Davey,Norman E. Davey +8 more
TL;DR: Interaction Modules Directing Cell Regulation Kim Van Roey, Bora Uyar,† Robert J. Weatheritt,‡ Holger Dinkel,† Markus Seiler,† Aidan Budd,† Toby J. Gibson,† and Norman E. Davey*.
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The role of proteases in transforming growth factor-β activation
TL;DR: The mechanism of protease driven TGF-beta activation is described, and the physiological and pathological relevance of this process is discussed.
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Transforming Growth Factor β1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression
Stephanie McMahon,Martine Charbonneau,Sebastien Grandmont,Darren E. Richard,Claire M. Dubois +4 more
TL;DR: A novel mechanism by which a growth factor controls HIF-1 stability, and thereby drives the expression of specific genes, through the regulation of PHD2 levels is revealed.
References
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Marcia M. Shull,Ilona Ormsby,Ann B. Kier,Sharon A. Pawlowski,Ronald J. Diebold,Moying Yin,Ruth D. Allen,Charles L. Sidman,Gabriele Proetzel,Dawn Calvin,Nikki Annunziata,Thomas Doetschman +11 more
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Ashok B. Kulkarni,Chang-Goo Huh,Dean Becker,Andrew G. Geiser,Marion Lyght,Kathleen C. Flanders,Anita B. Roberts,Michael B. Sporn,Jerrold M. Ward,Stefan Karlsson +9 more
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