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Closed Access item N-terminal cleavage of proTGFα occurs at the cell surface by a TACE-independent activity

Authors:Juanes, Pedro P.
Ferreira, Laura
Montero, Juan Carlos
Arribas, Joaquín
Pandiella, Atanasio
Issue Date:2005
Publisher:Biochemical Society
Citation:Biochemical Journal 389: 161-172 (2005)
Abstract:ProTGFα (transforming growth factor α precursor) maturation and conversion into soluble TGFα is a complex process that involves three proteolytic steps. One, that occurs co-translationally, eliminates the signal sequence. Another, occurring at the juxta-membrane domain, solubilizes TGFα. A third cleavage removes the N-terminal extension of proTGFα. This latter step has been poorly studied, mainly because of the rapid kinetics of this cleavage. In the present study, we have designed a strategy to analyse several aspects regarding this N-terminal cleavage. In vivo treatment with the hydroxamate-based metalloprotease inhibitors BB3103 or TAPI-2 (tumour necrosis factor-α protease inhibitor 2) reversibly induced accumulation of forms of proTGFα that included the N-terminal extension. N-terminal shedding was rapid, and occurred at the cell surface. However, the machinery resposible for the N-terminal cleavage was inactive in other cellular sites, such as the endoplasmic reticulum. Experiments of proTGFα expression and maturation in cells deficient in TACE (tumour-necrosis-factor-α-converting enzyme) activity indicated that this protease was dispensable for N-terminal processing of proTGFα in vivo, but was required for regulated cleavage at the C-terminus. These findings indicate that TACE is not involved in N-terminal processing of proTGFα, and suggest differences in the machineries that control the cleavage at both ends of TGFα within its precursor. © 2005 Biochemical Society.
Identifiers:doi: 10.1042/BJ20041128
issn: 0264-6021
e-issn: 1470-8728
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