Substrate Selectivity of Epidermal Growth Factor-Receptor Ligand Sheddases and their Regulation by Phorbol Esters and Calcium Influx

• DOI: 10.1091/mbc.e06-01-0014
• Publication Date: 2006-11-01T20:44:45Z
• Authors: Keisuke Horiuchi; Sylvain Le Gall; Marc Schulte; Takafumi Yamaguchi; Karina Reiss; Gillian Murphy; Yoshiaki Toyama; Dieter Hartmann; Paul Saftig; Carl P. Blobel
• Keywords: EGF Family of Proteins; 0303 health sciences; Epidermal Growth Factor; Ionophores; ADAM17 Protein; Ligands; Amphiregulin; Epiregulin; ErbB Receptors; ADAM Proteins; ADAM10 Protein; 03 medical and health sciences; Calmodulin; COS Cells; Chlorocebus aethiops; Animals; Intercellular Signaling Peptides and Proteins; Calcium; Amyloid Precursor Protein Secretases; Betacellulin; Glycoproteins; Heparin-binding EGF-like Growth Factor

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.