Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx

Keisuke Horiuchi, Sylvain Le Gall, Marc Schulte, Takafumi Yamaguchi, Karina Reiss, Gillian Murphy, Yoshiaki Toyama, Dieter Hartmann, Paul Saftig, Carl P. Blobel

Research output: Contribution to journalArticle

222 Citations (Scopus)

Abstract

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 we 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 transforming growth factor α and amphiregulin does not require ADAM17, even though ADAM17 is essential for phorbol ester-stimulated shedding of these EGFR-ligands. This study provides new insight into the machinery responsible for EGFR-ligand release and thus EGFR signaling and demonstrates that dysregulated EGFR-ligand shedding may be caused by increased expression of constitutively active sheddases or activation of different sheddases by distinct stimuli.

Original languageEnglish
Pages (from-to)176-188
Number of pages13
JournalMolecular Biology of the Cell
Volume18
Issue number1
DOIs
Publication statusPublished - 2007 Jan

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Phorbol Esters
Epidermal Growth Factor Receptor
Ligands
Calcium
Disintegrins
Secretory Pathway
Transforming Growth Factors
Metalloproteases
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. / Horiuchi, Keisuke; Le Gall, Sylvain; Schulte, Marc; Yamaguchi, Takafumi; Reiss, Karina; Murphy, Gillian; Toyama, Yoshiaki; Hartmann, Dieter; Saftig, Paul; Blobel, Carl P.

In: Molecular Biology of the Cell, Vol. 18, No. 1, 01.2007, p. 176-188.

Research output: Contribution to journalArticle

Horiuchi, K, Le Gall, S, Schulte, M, Yamaguchi, T, Reiss, K, Murphy, G, Toyama, Y, Hartmann, D, Saftig, P & Blobel, CP 2007, 'Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx', Molecular Biology of the Cell, vol. 18, no. 1, pp. 176-188. https://doi.org/10.1091/mbc.E06-01-0014
Horiuchi, Keisuke ; Le Gall, Sylvain ; Schulte, Marc ; Yamaguchi, Takafumi ; Reiss, Karina ; Murphy, Gillian ; Toyama, Yoshiaki ; Hartmann, Dieter ; Saftig, Paul ; Blobel, Carl P. / Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. In: Molecular Biology of the Cell. 2007 ; Vol. 18, No. 1. pp. 176-188.
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