TACE is required for the activation of the EGFR by TGF-α in tumors

The factors and mechanisms that transduce the intracellular signals sent upon activation of the receptor for the epidermal growth factor (EGFR) and related receptors are reasonably well understood and, in fact, are the targets of anti‐tumor drugs. In contrast, less is known about the mechanisms impl...

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Bibliographic Details
Published in:The EMBO journal 2003-03, Vol.22 (5), p.1114-1124
Main Authors: Borrell-Pagès, Maria, Rojo, Federico, Albanell, Joan, Baselga, Josep, Arribas, Joaquín
Format: Article
Language:English
Subjects:
ADAM Proteins
ADAM17 Protein
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinogenicity Tests
CHO Cells
Cricetinae
Culture Media, Conditioned
EGFR
EMBO24
EMBO37
Endopeptidases - genetics
Endopeptidases - metabolism
ErbB Receptors - genetics
ErbB Receptors - metabolism
Female
HeLa Cells
Humans
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases - genetics
Metalloendopeptidases - metabolism
metalloproteases
Mice
Mice, Nude
Neoplasms - metabolism
Neoplasms - pathology
shedding
TGF-α
Transforming Growth Factor alpha - metabolism
Transplantation, Heterologous
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Summary:The factors and mechanisms that transduce the intracellular signals sent upon activation of the receptor for the epidermal growth factor (EGFR) and related receptors are reasonably well understood and, in fact, are the targets of anti‐tumor drugs. In contrast, less is known about the mechanisms implicated in sending the signals that activate these receptors. Here we show that when its proteolytic shedding is prevented, the transmembrane form of the transforming growth factor‐α (proTGF‐α) interacts with, but does not activate, the EGFR. Thus, shedding seems to control not only the availability of the soluble form of the growth factor (TGF‐α) but also the activity of the transmembrane form. The activity of the protease responsible for the shedding of proTGF‐α, tumor necrosis factor‐α converting enzyme (TACE), is required for the activation of the EGFR in vivo and for the development of tumors in nude mice, indicating a crucial role of TACE in tumorigenesis. In agreement with this view, TACE is dramatically overexpressed in the majority of mammary tumors analyzed. Collectively, this evidence points to TACE as a promising target of anti‐tumor therapy.
ISSN:0261-4189
1460-2075
DOI:10.1093/emboj/cdg111