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Regular Articles |
From the Immunology Division*
and Department of
Pharmacology,
Faculty of Medicine,
Université de Sherbrooke, Sherbrooke; and the Laboratory of
Biochemical Neuroendocrinology,
Clinical
Research Institute of Montreal, Montreal, Quebec, Canada
Transforming growth factor (TGF)-ß1 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-ß1 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-ß1 convertase. Even though six
members of the PC family have the ability to cleave TGF-ß1,
ectopic expression of 
1-antitrypsin Portland
(1-AT-PDX), a potent furin inhibitor,
blocked 80% of TGF-ß1 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-ß1.
Moreover, both furin and TGF-ß 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-ß1-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-ß system and
should facilitate the development of therapeutically useful TGF-ß
inhibitors.
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D. E. Bassi, R. Lopez De Cicco, H. Mahloogi, S. Zucker, G. Thomas, and A. J. P. Klein-Szanto Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells PNAS, August 28, 2001; 98(18): 10326 - 10331. [Abstract] [Full Text] [PDF]
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