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A more recent version of this article appeared on January 1, 2007
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Submitted on January 6, 2006
Revised on September 25, 2006
Accepted on October 19, 2006
*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; ¶Departments of Medicine and of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
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 TGF
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.
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