Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx.
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.
Horiuchi
Keisuke
K
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Le Gall
Sylvain
S
Schulte
Marc
M
Yamaguchi
Takafumi
T
Reiss
Karina
K
Murphy
Gillian
G
Toyama
Yoshiaki
Y
Hartmann
Dieter
D
Saftig
Paul
P
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D066258:Amphiregulin; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000172:deficiency; D000818:Animals; D066259:Betacellulin; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002522:Chlorocebus aethiops; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency; D051379:Mice; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D066258:Amphiregulin; C587849:Areg protein, mouse; D066259:Betacellulin; C587852:Btc protein, mouse; D002147:Calmodulin; D066255:EGF Family of Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007476:Ionophores; D008024:Ligands; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium