title: Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx.
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.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Sylvain
authors.initials: S
authors.lastname: Le Gall
authors.forename: Marc
authors.initials: M
authors.lastname: Schulte
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: 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
chemical_list: 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