Title: Substrate Selectivity and Regulation of EGF-Receptor Ligand Sheddases by Phorbol Esters and Calcium Influx
Authors: Horiuchi, Keisuke ×
Le Gall, Sylvain
Schulte, Marc
Yamaguchi, Takafumi
Reiss, Karina
Murphy, Gillian
Toyama, Yoshiaki
Hartmann, Dieter
Saftig, Paul
Blobel, Carl P #
Issue Date: Jan-2007
Publisher: American Society for Cell Biology
Series Title: Molecular Biology of the Cell vol:18 issue:1 pages:176-188
Abstract: Monitoring Editor: Ben Margolis Signaling via the epidermal growth factor receptor (EGFR), which has critical roles in development and diseases such as cancer, is regulated by proteolytic shedding of its membrane-tethered ligands. Sheddases for EGFR-ligands are therefore key signaling switches in the EGFR pathway. Here, we determined which ADAMs (a disintegrin and metalloprotease) can shed various EGFR-ligands, and analyzed the regulation of EGFR-ligand shedding by two commonly used stimuli, phorbol esters and calcium influx. Phorbol esters predominantly activate ADAM17, thereby triggering a burst of shedding of EGFR-ligands from a late secretory pathway compartment. Calcium influx stimulates ADAM10, requiring its cytoplasmic domain. However, calcium-influx stimulated shedding of TGFalpha and amphiregulin does not require ADAM17, even though ADAM17 is essential for PMA-stimulated shedding of these EGFR-ligands. These results provide new insights into the machinery responsible for EGFR-ligand release and thus EGFR-signaling, and demonstrate that dysregulated EGFR-ligand shedding may be caused by increased expression of constitutively active sheddases or activation of different sheddases by distinct stimuli.
ISSN: 1059-1524
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
× corresponding author
# (joint) last author

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