期刊
MOLECULAR BIOLOGY OF THE CELL
卷 18, 期 1, 页码 176-188出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E06-01-0014
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资金
- NCRR NIH HHS [C06 RR012538, C06-RR12538-01] Funding Source: Medline
- NIGMS NIH HHS [R01 GM064750, R01 GM-64750] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR012538] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM064750] Funding Source: NIH RePORTER
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 a 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.
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