PMID- 28988771
OWN - NLM
STAT- MEDLINE
DCOM- 20171101
LR  - 20181202
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 171
IP  - 3
DP  - 2017 Oct 19
TI  - EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling 
      Kinetics.
PG  - 683-695.e18
LID - S0092-8674(17)31066-8 [pii]
LID - 10.1016/j.cell.2017.09.017 [doi]
AB  - Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, 
      with seven different activating ligands shaping cell signaling in distinct ways. 
      Using crystallography and other approaches, we show how the EGFR ligands 
      epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of 
      the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable 
      EGFR dimers than EGF-making them partial agonists of EGFR dimerization. 
      Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling 
      than seen with EGF, provoking responses in breast cancer cells associated with 
      differentiation rather than proliferation. Our results reveal how responses to 
      different EGFR ligands are defined by receptor dimerization strength and 
      signaling dynamics. These findings have broad implications for understanding 
      receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest 
      parallels between partial and/or biased agonism in RTKs and G-protein-coupled 
      receptors, as well as new therapeutic opportunities for correcting RTK signaling 
      output.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Freed, Daniel M
AU  - Freed DM
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, 
      USA.
FAU - Bessman, Nicholas J
AU  - Bessman NJ
AD  - Department of Biochemistry and Biophysics, University of Pennsylvania Perelman 
      School of Medicine, Philadelphia, PA 19104-6059, USA.
FAU - Kiyatkin, Anatoly
AU  - Kiyatkin A
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, 
      USA.
FAU - Salazar-Cavazos, Emanuel
AU  - Salazar-Cavazos E
AD  - Department of Pathology and UNM Comprehensive Cancer Center, University of New 
      Mexico Health Science Center, Albuquerque, NM 87131, USA.
FAU - Byrne, Patrick O
AU  - Byrne PO
AD  - Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 
      78712, USA.
FAU - Moore, Jason O
AU  - Moore JO
AD  - Department of Biochemistry and Biophysics, University of Pennsylvania Perelman 
      School of Medicine, Philadelphia, PA 19104-6059, USA.
FAU - Valley, Christopher C
AU  - Valley CC
AD  - Department of Pathology and UNM Comprehensive Cancer Center, University of New 
      Mexico Health Science Center, Albuquerque, NM 87131, USA.
FAU - Ferguson, Kathryn M
AU  - Ferguson KM
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, 
      USA.
FAU - Leahy, Daniel J
AU  - Leahy DJ
AD  - Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 
      78712, USA.
FAU - Lidke, Diane S
AU  - Lidke DS
AD  - Department of Pathology and UNM Comprehensive Cancer Center, University of New 
      Mexico Health Science Center, Albuquerque, NM 87131, USA.
FAU - Lemmon, Mark A
AU  - Lemmon MA
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, 
      USA; Department of Biochemistry and Biophysics, University of Pennsylvania 
      Perelman School of Medicine, Philadelphia, PA 19104-6059, USA. Electronic 
      address: mark.lemmon@yale.edu.
LA  - eng
GR  - P30 CA118100/CA/NCI NIH HHS/United States
GR  - U54 CA209992/CA/NCI NIH HHS/United States
GR  - R01 GM099092/GM/NIGMS NIH HHS/United States
GR  - R01 GM099321/GM/NIGMS NIH HHS/United States
GR  - R01 CA112552/CA/NCI NIH HHS/United States
GR  - U54 CA193417/CA/NCI NIH HHS/United States
GR  - R01 CA198164/CA/NCI NIH HHS/United States
GR  - F32 GM109688/GM/NIGMS NIH HHS/United States
GR  - P50 GM085273/GM/NIGMS NIH HHS/United States
GR  - T32 GM008275/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20171005
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (EPGN protein, human)
RN  - 0 (EREG protein, human)
RN  - 0 (Epigen)
RN  - 0 (Epiregulin)
RN  - 0 (Ligands)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Crystallography, X-Ray
MH  - Epigen/*chemistry/metabolism
MH  - Epiregulin/*chemistry/metabolism
MH  - ErbB Receptors/*chemistry/*metabolism
MH  - Fluorescence Resonance Energy Transfer
MH  - Humans
MH  - Kinetics
MH  - Ligands
MH  - Models, Molecular
MH  - Protein Multimerization
PMC - PMC5650921
MID - NIHMS906573
OTO - NOTNLM
OT  - biased agonist
OT  - cell fate decision
OT  - crystallography
OT  - dimerization
OT  - growth factor
OT  - kinetic proofreading
OT  - negative feedback
OT  - phosphatase
OT  - receptor tyrosine kinase
OT  - signaling specificity
EDAT- 2017/10/11 06:00
MHDA- 2017/11/02 06:00
PMCR- 2018/10/19
CRDT- 2017/10/10 06:00
PHST- 2017/05/06 00:00 [received]
PHST- 2017/07/31 00:00 [revised]
PHST- 2017/09/12 00:00 [accepted]
PHST- 2017/10/11 06:00 [pubmed]
PHST- 2017/11/02 06:00 [medline]
PHST- 2017/10/10 06:00 [entrez]
PHST- 2018/10/19 00:00 [pmc-release]
AID - S0092-8674(17)31066-8 [pii]
AID - 10.1016/j.cell.2017.09.017 [doi]
PST - ppublish
SO  - Cell. 2017 Oct 19;171(3):683-695.e18. doi: 10.1016/j.cell.2017.09.017. Epub 2017 
      Oct 5.