Metalloprotease-dependent Protransforming Growth
Factor-
Ectodomain Shedding in the Absence of Tumor Necrosis
Factor--converting Enzyme*
Anna
Merlos-Suárez
,
Soraya
Ruiz-Paz,
José
Baselga, and
Joaquín
Arribas§
From the Laboratori de Recerca Oncològica, Servei
d'Oncologia Mèdica, Hospital Universitari Vall d'Hebron,
Psg. Vall d'Hebron 119-129, Barcelona 08035, Spain
Zinc-dependent metalloproteases can
mediate the shedding of the extracellular domain of many unrelated
transmembrane proteins from the cell surface. In most instances, this
process, also known as ectodomain shedding, is regulated via protein
kinase C (PKC). The tumor necrosis factor 
-converting enzyme (TACE)
was the first protease involved in regulated protein ectodomain
shedding identified. Although TACE belongs to the family of
metalloprotease-disintegrins, few members of this family have been
shown to participate in regulated ectodomain shedding. In fact, the
phenotype of tace
/ cells and that of Chinese hamster
ovary cell mutants defective in ectodomain shedding points to
the existence of a common PKC-activated ectodomain shedding system,
whose proteolytic component is TACE, that acts on a variety of
transmembrane proteins. Examples of these proteins include the
Alzheimer's disease-related protein 
-amyloid precursor protein
(APP) and the transmembrane growth factors protransforming growth
factor- (pro-TGF-) and, as shown in this report,
proheparin-binding epidermal growth factor-like growth factor
(pro-HB-EGF). Here we show that the mercurial compound
4-aminophenylmercuric acetate (APMA), frequently used to activate
in vitro recombinant matrix metalloproteases, is an
activator of the shedding of APP, pro-HB-EGF, and pro-TGF-.
Treatment of tace/ cells or Chinese hamster ovary shedding-defective mutants with APMA activates the cleavage of pro-TGF- but not that of pro-HB-EGF or APP, indicating that APMA
activates TACE and also a previously unacknowledged proteolytic activity specific for pro-TGF-. Characterization of this proteolytic activity indicates that it acts on pro-TGF- located at the cell surface and that it is a metalloprotease active in cells defective in
furin activity. In summary, treatment of shedding-defective cell lines
with APMA unveils the existence of a metalloprotease activity
alternative to TACE with the ability to specifically shed the
ectodomain of pro-TGF-.
*
This work was supported by grants from the Spanish
Comisión Interministerial de Ciencia y Tecnología
(SAF2000-0203), Fundació La Marató de TV3 (036/97), and
Fundació "la Caixa" (98/056-01) (to J. A.), a predoctoral
fellowship from the Spanish Ministry of Education (to A. M.-S.), and a
predoctoral fellowship from Fundació per la Recerca i
Docència dels Hospitals Vall d'Hebron (to S. R.-P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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