PMID- 26477568
OWN - NLM
STAT- MEDLINE
DCOM- 20160819
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 5
DP  - 2015 Oct 19
TI  - Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using 
      recombinant ADAM12 prodomain.
PG  - 15150
LID - 10.1038/srep15150 [doi]
LID - 15150
AB  - Dysregulation of ErbB-family signaling underlies numerous pathologies and has 
      been therapeutically targeted through inhibiting ErbB-receptors themselves or 
      their cognate ligands. For the latter, "decoy" antibodies have been developed to 
      sequester ligands including heparin-binding epidermal growth factor (HB-EGF); 
      however, demonstrating sufficient efficacy has been difficult. Here, we 
      hypothesized that this strategy depends on properties such as ligand-receptor 
      binding affinity, which varies widely across the known ErbB-family ligands. 
      Guided by computational modeling, we found that high-affinity ligands such as 
      HB-EGF are more difficult to target with decoy antibodies compared to 
      low-affinity ligands such as amphiregulin (AREG). To address this issue, we 
      developed an alternative method for inhibiting HB-EGF activity by targeting its 
      cleavage from the cell surface. In a model of the invasive disease endometriosis, 
      we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease 
      implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based 
      on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not 
      ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF 
      shedding and resultant cellular migration. Overall, specific inhibition of ligand 
      shedding represents a possible alternative to decoy antibodies, especially for 
      ligands such as HB-EGF that exhibit high binding affinity and localized 
      signaling.
FAU - Miller, Miles A
AU  - Miller MA
AD  - Massachusetts Institute of Technology, Department of Biological Engineering, 77 
      Massachusetts Ave., Cambridge, MA 02139.
FAU - Moss, Marcia L
AU  - Moss ML
AD  - BioZyme, Inc., 1513 Old White Oak Church Road, Apex, NC 27523.
FAU - Powell, Gary
AU  - Powell G
AD  - National Institutes of Environmental Health Services (NIEHS), 111 TW Alexander 
      Dr. RTP, NC 27709.
FAU - Petrovich, Robert
AU  - Petrovich R
AD  - National Institutes of Environmental Health Services (NIEHS), 111 TW Alexander 
      Dr. RTP, NC 27709.
FAU - Edwards, Lori
AU  - Edwards L
AD  - National Institutes of Environmental Health Services (NIEHS), 111 TW Alexander 
      Dr. RTP, NC 27709.
FAU - Meyer, Aaron S
AU  - Meyer AS
AD  - Massachusetts Institute of Technology, Department of Biological Engineering, 77 
      Massachusetts Ave., Cambridge, MA 02139.
FAU - Griffith, Linda G
AU  - Griffith LG
AD  - Massachusetts Institute of Technology, Department of Biological Engineering, 77 
      Massachusetts Ave., Cambridge, MA 02139.
FAU - Lauffenburger, Douglas A
AU  - Lauffenburger DA
AD  - Massachusetts Institute of Technology, Department of Biological Engineering, 77 
      Massachusetts Ave., Cambridge, MA 02139.
LA  - eng
GR  - R01 CA096504/CA/NCI NIH HHS/United States
GR  - U54 CA112967/CA/NCI NIH HHS/United States
GR  - R01-CA096504/CA/NCI NIH HHS/United States
GR  - U54-CA112967/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20151019
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Amphiregulin)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Heparin-binding EGF-like Growth Factor)
RN  - 0 (Ligands)
RN  - 0 (Membrane Proteins)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (ADAM12 Protein)
RN  - EC 3.4.24.- (ADAM12 protein, human)
SB  - IM
MH  - ADAM Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - ADAM12 Protein
MH  - Amphiregulin/pharmacology
MH  - Antibodies, Monoclonal/pharmacology
MH  - *Autocrine Communication
MH  - Cell Line
MH  - Cell Movement/drug effects
MH  - Endometriosis/genetics/metabolism
MH  - Endometrium/cytology/drug effects/metabolism
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Heparin-binding EGF-like Growth Factor/*metabolism
MH  - Humans
MH  - Ligands
MH  - Membrane Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Models, Biological
MH  - Protein Binding
MH  - Recombinant Proteins/*pharmacology
MH  - Signal Transduction/*drug effects
PMC - PMC4609913
EDAT- 2015/10/20 06:00
MHDA- 2016/08/20 06:00
PMCR- 2015/10/19
CRDT- 2015/10/20 06:00
PHST- 2015/01/23 00:00 [received]
PHST- 2015/09/07 00:00 [accepted]
PHST- 2015/10/20 06:00 [entrez]
PHST- 2015/10/20 06:00 [pubmed]
PHST- 2016/08/20 06:00 [medline]
PHST- 2015/10/19 00:00 [pmc-release]
AID - srep15150 [pii]
AID - 10.1038/srep15150 [doi]
PST - epublish
SO  - Sci Rep. 2015 Oct 19;5:15150. doi: 10.1038/srep15150.