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Vol. 18, Issue 1, 176-188, January 2007

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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, and Carl P. Blobel^*,¶

*Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021; Biochemical Institute, Christian-Albrechts University, D-24098 Kiel, Germany; Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, 160-8582 Japan; Cambridge Institute for Medical Research, Cambridge CB2 2XY, United Kingdom; ^||Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium; and ^¶Departments of Medicine and of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021

Submitted January 6, 2006; Revised September 25, 2006; Accepted October 19, 2006
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 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 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.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-01-0014) on November 1, 2006.

Address correspondence to: Carl P. Blobel (blobelc{at}hss.edu)

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