Abstract
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 alpha 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / chemistry
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ADAM Proteins / deficiency
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ADAM Proteins / metabolism*
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ADAM10 Protein
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ADAM17 Protein
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Amphiregulin
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / deficiency
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Animals
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Betacellulin
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COS Cells
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Calcium / metabolism*
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Calmodulin / antagonists & inhibitors
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Chlorocebus aethiops
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EGF Family of Proteins
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Epidermal Growth Factor / metabolism
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Epiregulin
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ErbB Receptors / metabolism*
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Glycoproteins / metabolism
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins / metabolism
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Ionophores / pharmacology
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Ligands
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Membrane Proteins / chemistry
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Membrane Proteins / deficiency
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Mice
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Protein Structure, Tertiary / drug effects
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Recombinant Fusion Proteins / metabolism
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Substrate Specificity / drug effects
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Tetradecanoylphorbol Acetate / pharmacology*
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Transforming Growth Factor alpha / metabolism
Substances
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Amphiregulin
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Areg protein, mouse
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Betacellulin
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Btc protein, mouse
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Calmodulin
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EGF Family of Proteins
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Epiregulin
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Ereg protein, mouse
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Glycoproteins
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Ionophores
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Ligands
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Membrane Proteins
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Recombinant Fusion Proteins
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Transforming Growth Factor alpha
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Epidermal Growth Factor
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ErbB Receptors
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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Adam10 protein, mouse
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ADAM17 Protein
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Adam17 protein, mouse
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Tetradecanoylphorbol Acetate
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Calcium