Substrate Selectivity and Regulation of EGF-Receptor Ligand Sheddases 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 #
American Society for Cell Biology
Molecular Biology of the Cell vol:18 issue:1 pages:176-188
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.