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 juxtamembrane 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 responsible 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.
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Research Article|
June 21 2005
N-terminal cleavage of proTGFα occurs at the cell surface by a TACE-independent activity
Pedro P. JUANES;
Pedro P. JUANES
1
*Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007-Salamanca, Spain
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Laura FERREIRA;
Laura FERREIRA
1
*Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007-Salamanca, Spain
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Juan Carlos MONTERO;
Juan Carlos MONTERO
*Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007-Salamanca, Spain
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Joaquín ARRIBAS;
Joaquín ARRIBAS
†Medical Oncology Research Program, Vall d'Hebron University Research Hospital Research Institute, Psg. Vall d'Hebron 119-129, Barcelona 08035, Spain
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Atanasio PANDIELLA
Atanasio PANDIELLA
2
*Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007-Salamanca, Spain
2To whom correspondence should be addressed (email atanasio@usal.es).
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Publisher: Portland Press Ltd
Received:
July 01 2004
Revision Received:
March 02 2005
Accepted:
March 18 2005
Accepted Manuscript online:
March 18 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 389 (1): 161–172.
Article history
Received:
July 01 2004
Revision Received:
March 02 2005
Accepted:
March 18 2005
Accepted Manuscript online:
March 18 2005
Citation
Pedro P. JUANES, Laura FERREIRA, Juan Carlos MONTERO, Joaquín ARRIBAS, Atanasio PANDIELLA; N-terminal cleavage of proTGFα occurs at the cell surface by a TACE-independent activity. Biochem J 1 July 2005; 389 (1): 161–172. doi: https://doi.org/10.1042/BJ20041128
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